General Information of the Disease (ID: DIS00033)
Name
Lung cancer
ICD
ICD-11: 2C25
Full List of Target(s) of This Ferroptosis-centered Disease
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
In total 20 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Lactate Investigative
Responsed Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Driver
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H446 cells Lung small cell carcinoma Homo sapiens CVCL_1562
NCI-H1688 cells Lung small cell carcinoma Homo sapiens CVCL_1487
Response regulation Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in Non-Small Cell Lung Cancer (NSCLC). Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38 (MAPK14)-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Lactate Investigative
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H446 cells Lung small cell carcinoma Homo sapiens CVCL_1562
NCI-H1688 cells Lung small cell carcinoma Homo sapiens CVCL_1487
Response regulation Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in Non-Small Cell Lung Cancer (NSCLC). Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38 (MAPK14)-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Propofol Investigative
Responsed Regulator hsa-miR-744-5p (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
BALB/c nude mice (5 weeks) were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. (license no: SYXK (Beijing) 20170033). For tumor formation, 8 x 106 A549/Cis cells were subcutaneously injected into the right axilla of each mouse. On the 7th d, Cis (4.0 mg/kg) was intraperitoneally injected into each mouse every 4 days. Then, mice were allocated into 3 groups: Control group (no additional injection); SO group (intraperitoneal injection of soybean oil); and Propofol group [intraperitoneal injection of soybean oil-dissolved propofol (35 mg/kg)]. The volume of the tumor was measured by a caliper every 7 days. Tumor volume was measured according to the formula: V (mm3) = 1/2 ab2 (a: the longest axis of tumor; b: the shortest axis of tumor). Then 35 d after transplantation, mice were euthanatized to measure tumor weight using an electronic balance. A part of transplanted tumors was immediately conserved at liquid nitrogen and -80 . The rest was used for paraffin-embedding and immunohistochemical staining.

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Response regulation In summary, propofol inhibited GPX4-mediated ferroptosis and reduces CR of non-small cell lung cancer (NSCLC) cells to Cis through the miR-744-5p/miR-615-3p axis.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Propofol Investigative
Responsed Regulator hsa-miR-615-3p (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
BALB/c nude mice (5 weeks) were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. (license no: SYXK (Beijing) 20170033). For tumor formation, 8 x 106 A549/Cis cells were subcutaneously injected into the right axilla of each mouse. On the 7th d, Cis (4.0 mg/kg) was intraperitoneally injected into each mouse every 4 days. Then, mice were allocated into 3 groups: Control group (no additional injection); SO group (intraperitoneal injection of soybean oil); and Propofol group [intraperitoneal injection of soybean oil-dissolved propofol (35 mg/kg)]. The volume of the tumor was measured by a caliper every 7 days. Tumor volume was measured according to the formula: V (mm3) = 1/2 ab2 (a: the longest axis of tumor; b: the shortest axis of tumor). Then 35 d after transplantation, mice were euthanatized to measure tumor weight using an electronic balance. A part of transplanted tumors was immediately conserved at liquid nitrogen and -80 . The rest was used for paraffin-embedding and immunohistochemical staining.

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Response regulation In summary, propofol inhibited GPX4-mediated ferroptosis and reduces CR of non-small cell lung cancer (NSCLC) cells to Cis through the miR-744-5p/miR-615-3p axis.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Tetraarsenic tetrasulfide Investigative
Responsed Regulator RAF proto-oncogene serine/threonine-protein kinase (RAF1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
MAPK signaling pathway hsa04010
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in antiKRAS mutant lung cancer.
Experiment 6 Reporting the Ferroptosis-centered Disease Response by This Target [25]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Orlistat Approved
Pathway Response Fatty acid metabolism hsa01212
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
LL/2 (LLC1) cells Lung cancer Mus musculus CVCL_4358
In Vivo Model
C57BL/6 mice were anesthetized, and 5 x 105 LLC cells were implanted subcutaneously into the right flank. Five days post-implant, mice were randomized and assigned into two groups and treated with orlistat (10 mg/kg, intraperitoneal injection) or PBS daily for 14 days. The tumor volume was measured twice a week with a caliper, and the tumor volume was calculated according to the formula ((length x width2 )/2).

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Response regulation Orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation.
Experiment 7 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Betulin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRASmutant non-small-cell lung cancer (NSCLC) cells.
Experiment 8 Reporting the Ferroptosis-centered Disease Response by This Target [27]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Capsaicin Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
Response regulation Capsaicin inhibited the proliferation of A549 and NCI-H23 cells and induced ferroptosis by inactivating SLC7A11/GPX4 signaling. Capsaicin could be used as a potential anticancer agent in the treatment of non-small cell lung cancer (NSCLC).
Experiment 9 Reporting the Ferroptosis-centered Disease Response by This Target [28]
Target for Ferroptosis Suppressor
Responsed Disease Lung mucoepidermoid carcinoma [ICD-11: 2C25]
Responsed Drug Dihydroartemisinin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell proliferation
Cell autophagy
In Vitro Model NCI-H292 cells Lung mucoepidermoid carcinoma Homo sapiens CVCL_0455
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
HT29 cells Colon cancer Mus musculus CVCL_A8EZ
SW480 cells Colon adenocarcinoma Homo sapiens CVCL_0546
MDA-MB-453 cells Breast adenocarcinoma Homo sapiens CVCL_0418
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
In Vivo Model
GPX4 iKO H292 cells were inoculated by injecting 3 x 106 cells in 0.1 mL PBS subcutaneously in the right flank of six- to eight-week-old female athymic nude Foxn1nu/Foxn1 mice (Envigo, East Millstone, NJ, USA). Following inoculation, the mice were monitored until they have fully recovered and are moving. Mice were randomly allocated into their respective groups (non-blinded). Tumor growth was monitored regularly via external caliper measurements.

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Response regulation Dihydroartemisinin (DAT) can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis in Lung mucoepidermoid carcinoma.
Experiment 10 Reporting the Ferroptosis-centered Disease Response by This Target [29]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Dihydroartemisinin Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
Response regulation Dihydroartemisinin (DHA) treatment decreased the levels of GPX4, DHA significantly induced apoptosis and ferroptosis in a dose-dependent manner and exhibited high cellular toxicity on A549-GR (non-small cell lung cancer) cells when combined with gefitinib.
Experiment 11 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Gefitinib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRASmutant non-small-cell lung cancer (NSCLC) cells.
Experiment 12 Reporting the Ferroptosis-centered Disease Response by This Target [30]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Ginkgetin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
In Vivo Model
Briefly, when tumours on transplanted nude mice reached around 100 mm3, the mice were randomized divided into eight groups: control, ginkgetin, DDP, ginkgetin + DDP, UAMC 3203, ginkgetin + UAMC 3203, DDP + UAMC 3203, ginkgetin + DDP + UAMC 3203. Both DDP (3 mg/kg) and ginkgetin (30 mg/kg) were administered by intraperitoneal injection, with 2 - 3 times per week and once per day, respectively. UAMC 3203 (10 mg/kg) was administered 5 days/week by intraperitoneally injection. Tumour size and body weight were measured 3 times per week. After dosing 31 days, the nude mice were sacrificed, and tumours were removed and weighed.

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Response regulation The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured non-small cell lung cancer (NSCLC) cells.
Experiment 13 Reporting the Ferroptosis-centered Disease Response by This Target [31]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25]
Responsed Regulator Protein LYRIC (MTDH) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
DMS53 cells Lung small cell carcinoma Homo sapiens CVCL_1177
DMS 273 cells Lung small cell carcinoma Homo sapiens CVCL_1176
KLE cells Endometrial adenocarcinoma Homo sapiens CVCL_1329
AN3CA cells Endometrial adenocarcinoma Homo sapiens CVCL_0028
RL95-2 cells Endometrial adenosquamous carcinoma Homo sapiens CVCL_0505
HEC-1-A cells Endometrial adenocarcinoma Homo sapiens CVCL_0293
Ishikawa cells Endometrial adenocarcinoma Homo sapiens CVCL_2529
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Hec50 cells Endometrial adenocarcinoma Homo sapiens CVCL_2929
In Vivo Model
To generate tumor xenograft models, 5 x 106 MTDH WT and KO MDA-MB-231 cells were injected into the second and fifth mammary fat pads (both sides, total four sites) of the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG, Jackson Laboratories, Bar Harbor, ME) immunodeficient female mice. To study the metastasis from this orthotopic mouse model, tumor volumes were allowed to grow to ~1000 mm3, after which livers were resected to examine incidence as well as tumor burden of liver metastasis.

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Response regulation Metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system Xc-heterodimerization partner), at both the messenger RNA and protein levels in Lung adenocarcinoma.
Experiment 14 Reporting the Ferroptosis-centered Disease Response by This Target [32]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Epidermal growth factor receptor (EGFR) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model hTERT-HME1 cells Normal Homo sapiens CVCL_3383
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
In Vivo Model
2.5 x 105 NCI-H1650 cells were inoculated 1:1 in Matrigel: PBS (100 mL) by subcutaneous injection into eight non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma male mice. Tumors were allowed to engraft and grow for 30 days (tumor volume averaged ~200 mm3) and mice treated by intraperitoneal (i.p.) injection with 100 mg/kg cyst(e)inase or 100 mg/kg heat-inactivated cyst(e)inase (n = 4 ea.) on day 30, with a second dose given on day 33. Mice were necropsied 24 hr after the second dose.

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Response regulation In non-small-cell lung cancer (NSCLC) cells, active MAPK signaling downstream of active EGFR can sensitize cells to ferroptosis upon cystine depletion. Sensitization involves both impaired detoxification of lipid peroxides, due to reduced expression of GPX4, and generation of hydrogen peroxide, via NOX4.
Experiment 15 Reporting the Ferroptosis-centered Disease Response by This Target [33]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-324-3p (miRNA) Driver
Pathway Response Glutathione metabolism hsa00480
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
A549-CR cells Lung adenocarcinoma Homo sapiens CVCL_IP03
Response regulation MiR-324-3p was able to reduce the viability and increase death of cisplatin-resistant A549 cells. Its function may be exerted through its direct binding to GPX4, a key regulator of ferroptosis. MiR-324-3p could serve as a potential target in the treatment of non small cell lung cancer (NSCLC).
Experiment 16 Reporting the Ferroptosis-centered Disease Response by This Target [34]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cyclic AMP-responsive element-binding protein 1 (CREB1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
MRC-5 cells Normal Homo sapiens CVCL_0440
WI-38 cells Normal Homo sapiens CVCL_0579
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
NCI-H226 cells Pleural epithelioid mesothelioma Homo sapiens CVCL_1544
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation It was observed that CREB (CREB1, CREB3 and CREB5) suppressed lipid peroxidation by binding the promoter region of glutathione peroxidase 4 (GPX4), and this binding could be enhanced by E1A binding protein P300 (EP300). Therefore, targeting this CREB/EP300/GPX4 axis may provide new strategies for treating lung adenocarcinoma.
Experiment 17 Reporting the Ferroptosis-centered Disease Response by This Target [34]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cyclic AMP-responsive element-binding protein 3 (CREB3) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
MRC-5 cells Normal Homo sapiens CVCL_0440
WI-38 cells Normal Homo sapiens CVCL_0579
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
NCI-H226 cells Pleural epithelioid mesothelioma Homo sapiens CVCL_1544
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation It was observed that CREB (CREB1, CREB3 and CREB5) suppressed lipid peroxidation by binding the promoter region of glutathione peroxidase 4 (GPX4), and this binding could be enhanced by E1A binding protein P300 (EP300). Therefore, targeting this CREB/EP300/GPX4 axis may provide new strategies for treating lung adenocarcinoma.
Experiment 18 Reporting the Ferroptosis-centered Disease Response by This Target [34]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cyclic AMP-responsive element-binding protein 5 (CREB5) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
MRC-5 cells Normal Homo sapiens CVCL_0440
WI-38 cells Normal Homo sapiens CVCL_0579
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
NCI-H226 cells Pleural epithelioid mesothelioma Homo sapiens CVCL_1544
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation It was observed that CREB (CREB1, CREB3 and CREB5) suppressed lipid peroxidation by binding the promoter region of glutathione peroxidase 4 (GPX4), and this binding could be enhanced by E1A binding protein P300 (EP300). Therefore, targeting this CREB/EP300/GPX4 axis may provide new strategies for treating lung adenocarcinoma.
Experiment 19 Reporting the Ferroptosis-centered Disease Response by This Target [35]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator CircDTL (circRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The Shanghai SLAC Animal Center (Shanghai, China) provided 4-6-week-old BALB/c male nude mice, which were kept according to the standards for the use and care of laboratory animals. A total of 1 x 107 NSCLC cells infected with shRNA were injected subcutaneously into the left flank of nude mice (3 per group). Every 3 days, the tumor volume was measured.

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Response regulation It was identified that circDTL exerts its oncogenic effects via the circDTL/miR-1287-5p/GPX4 axis and GPX4 inhibits both ferroptosis and apoptosis. Finally, silencing of circDTL promoted the sensitivity of non-small cell lung cancer cells to chemotherapeutic agents and inhibited the growth of tumors in vivo.
Experiment 20 Reporting the Ferroptosis-centered Disease Response by This Target [35]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-1287-5p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The Shanghai SLAC Animal Center (Shanghai, China) provided 4-6-week-old BALB/c male nude mice, which were kept according to the standards for the use and care of laboratory animals. A total of 1 x 107 NSCLC cells infected with shRNA were injected subcutaneously into the left flank of nude mice (3 per group). Every 3 days, the tumor volume was measured.

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Response regulation It was identified that circDTL exerts its oncogenic effects via the circDTL/miR-1287-5p/GPX4 axis and GPX4 inhibits both ferroptosis and apoptosis. Finally, silencing of circDTL promoted the sensitivity of non-small cell lung cancer cells to chemotherapeutic agents and inhibited the growth of tumors in vivo.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
In total 14 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Drug RSL3 Investigative
Responsed Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H2122 cells Lung adenocarcinoma Homo sapiens CVCL_1531
In Vivo Model
After two weeks in house, the mice were subcutaneously injected with A549 cells (100 uL containing 5 x 106 cells/injection) and monitored for tumor cell xenografts to reach approximately 100 mm3. The mice were then divided into two groups (n = 5), the RSL3 treatment (100 mg/kg; dissolved in 5% dimethyl sulfoxide/corn oil; administrated intratumorally twice a day for one week) and control (5% dimethyl sulfoxide/corn oil only) groups.

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Response regulation RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK lung adenocarcinoma cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [5]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Isoorientin Investigative
Responsed Regulator NAD-dependent protein deacylase sirtuin-6 (SIRT6) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The A549/DDP tumor cells were subcutaneously injected (2 x 106 cells/mL) into BALB/c-nu mice under aseptic conditions. 6 days later, the average diameter of the tumor reaches 0.5 cm, and the mice were randomly divided into the 1 mg/kg DDP group and the 1 mg/kg DDP + 25mg/kg IO group. Six mice from each group were intraperitoneally administered medications every 2 days for a total of 10 doses each.

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Response regulation Isoorientin (IO) can promote ferroptosis and reverse drug resistance in lung cancer through the SIRT6/Nrf2/GPX4 signaling pathway, thus offering a theoretical basis for its potential clinical application.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [6]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug zero-valent-iron nanoparticle Investigative
Responsed Regulator 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
mTOR signaling pathway hsa04150
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
A9 cells Lung carcinoma Mus musculus CVCL_S007
MRC-5 cells Normal Homo sapiens CVCL_0440
IMR-90 cells Normal Homo sapiens CVCL_0347
In Vivo Model
5-6-week-old BALB/c nude mice (ZVI@Ag treatment) or NOD/SCID mice (ZVI@CMC treatment) were subcutaneously implanted with 1 x 106 H460 cells. For A549 xenograft model of immunodeficient mouse and spontaneous lung metastasis model, 5-6-week-old NOD/SCID mice were subcutaneously implanted with 5 x 106 A549 cells. For experimental lung metastasis model, H460 cells (1 x 106 cells/200 uL) were resuspended in serum-free medium and injected intravenously (i.v.) into tail-vein of NOD/SCID mice. For subcutaneous model of immunocompetent mouse, LLC cells (5 x 105) were injected into both flank of 6-week-old C57BL/6 mice.

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Response regulation Zero-valent-iron nanoparticle (ZVI-NP) triggered ferroptosis selectively in lung cancer cells by suppressing NRF2-mediated cytoprotection program, which was attributed to the ZVI-NP-induced disruption of PRKAA1 (AMPK)/mTOR signaling and activation of GSK3/-TrCP-dependent degradation system.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [36]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Manoalide Phase 2
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H157 cells Oral cavity Squamous cell carcinoma Homo sapiens CVCL_2458
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
The LSL-KrasG12D mouse model was obtained from the Jackson Laboratory (Sacramento, CA). Adeno-Cre (Genechem, Shanghai, China) was introduced into the trachea of mice at a dose of 1.25 x 1011 PFU in a total volume of 50 uL. Tumor tissues from 12-week post-infection mice were washed with cold PBS, cut into small pieces, and washed with DMEM/F12 (containing 1 x Glutamine, 10 mM HEPES, and antibiotics), digested with collagenase I and IV for 0.5-1 h at 37. After washing twice with DMEM/F12 and centrifugation (500 g, 5 min), the dissociated cells were seeded into growth factor-reduced matrigel (Corning, #356237) at 37 for 30 min.

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Response regulation Manoalide (MA) induces ferroptosis by suppressing the NRF2-SLC7A11 axis and mitochondrial Ca2+overload induced-FTH1 pathways to promote the sensitivity of osimertinib-resistant lung cancer cells to osimertinib.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [37]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Erastin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
A total of 60 BALB/c-nu/nu nude mice (male; age, 4-6 weeks; weight, 16-22 g) were obtained from the Shanghai Laboratory Animal Co., Ltd. N5CP cells (5 x 106) were suspended in 200 ul DMEM and Matrigel mixture at a ratio of 1:1. Subsequently, the mixture was injected subcutaneously into the upper right flank of 20 nude mice. After 10 days, the mice were randomly divided into four groups and were treated with CDDP (5 mg/kg/2 days), erastin (10 mg/kg/2 days), sorafenib (10 mg/kg/2 days) or PBS by intraperitoneal injection. Two days after the third injection, the mice were sacrificed and tumours were carefully removed. For the combination experiment, CDDP (1 mg/kg) and erastin (5 mg/kg) or sorafenib (3 mg/kg) were also injected three times.

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Response regulation The potential mechanism by which sorafenib and erastin induced ferroptosis in cisplatin (CDDP)-resistant non-small cell lung cancer (NSCLC) cells may be associated with inhibition of the expression of the Nrf2 downstream target gene xCT.
Experiment 6 Reporting the Ferroptosis-centered Disease Response by This Target [30]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Ginkgetin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
In Vivo Model
Briefly, when tumours on transplanted nude mice reached around 100 mm3, the mice were randomized divided into eight groups: control, ginkgetin, DDP, ginkgetin + DDP, UAMC 3203, ginkgetin + UAMC 3203, DDP + UAMC 3203, ginkgetin + DDP + UAMC 3203. Both DDP (3 mg/kg) and ginkgetin (30 mg/kg) were administered by intraperitoneal injection, with 2 - 3 times per week and once per day, respectively. UAMC 3203 (10 mg/kg) was administered 5 days/week by intraperitoneally injection. Tumour size and body weight were measured 3 times per week. After dosing 31 days, the nude mice were sacrificed, and tumours were removed and weighed.

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Response regulation The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured non-small cell lung cancer (NSCLC) cells.
Experiment 7 Reporting the Ferroptosis-centered Disease Response by This Target [38]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
When tumor volumes in xenograft nude mice reached an average of roughly 100 mm3, the mice were randomly divided into 3 groups of 6 mice each: control, ShtIX, and ShtIX + Fer-1. The treated group received ShtIX or ShtIX combined with Fer-1 injections into the tail vein of the mice every three days for 7 times, whereas the control group received saline. Every four days, the volume and weight of the tumors were measured. As soon as the test was completed, the nude mice were slaughtered, and the tumor tissues were retrieved. The in vivo experiments were approved by the Animal Care and Use Committee of Hainan Medical College and following the animal rules.

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Response regulation S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane (ShtIX) caused ferroptosis in Non-small cell lung cancer (NSCLC) cells, and inhibiting the Nrf2/HO-1 pathway can considerably exacerbate the effect of ShtIX-induced ferroptosis.
Experiment 8 Reporting the Ferroptosis-centered Disease Response by This Target [37]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Sorafenib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
A total of 60 BALB/c-nu/nu nude mice (male; age, 4-6 weeks; weight, 16-22 g) were obtained from the Shanghai Laboratory Animal Co., Ltd. N5CP cells (5 x 106) were suspended in 200 ul DMEM and Matrigel mixture at a ratio of 1:1. Subsequently, the mixture was injected subcutaneously into the upper right flank of 20 nude mice. After 10 days, the mice were randomly divided into four groups and were treated with CDDP (5 mg/kg/2 days), erastin (10 mg/kg/2 days), sorafenib (10 mg/kg/2 days) or PBS by intraperitoneal injection. Two days after the third injection, the mice were sacrificed and tumours were carefully removed. For the combination experiment, CDDP (1 mg/kg) and erastin (5 mg/kg) or sorafenib (3 mg/kg) were also injected three times.

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Response regulation The potential mechanism by which sorafenib and erastin induced ferroptosis in cisplatin (CDDP)-resistant non-small cell lung cancer (NSCLC) cells may be associated with inhibition of the expression of the Nrf2 downstream target gene xCT.
Experiment 9 Reporting the Ferroptosis-centered Disease Response by This Target [39]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung large cell carcinoma [ICD-11: 2C25]
Responsed Regulator Tumor suppressor ARF (CDKN2A) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HEK293 cells Normal Homo sapiens CVCL_0045
SAOS-2 cells Osteosarcoma Homo sapiens CVCL_0548
U2OS cells Osteosarcoma Homo sapiens CVCL_0042
In Vivo Model
Pooled stable cell line was derived from H1299 tet-on ARF cells by transfecting either empty vector or vector overexpressing NRF2. Cells were selected by G418 (1 mg /ml) for 2 weeks and then re-transfected the same vectors again. After additional treatment with or without doxycycline (1.0 mg/ml) for 60 h, 1.0 x 106 of cells were then mixed with Matrigel (BD Biosciences) at 1:1 ratio (volume) and injected subcutaneously into nude mice (NU/NU, Charles River). The mice were fed with the food containing doxycycline hyclate (Harlan, 625 mg/kg) or control food.

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Response regulation ARF (CDKN2A) expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses in lung large cell carcinoma cell lines.
Experiment 10 Reporting the Ferroptosis-centered Disease Response by This Target [39]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung large cell carcinoma [ICD-11: 2C25]
Responsed Regulator Tumor suppressor ARF (CDKN2A) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HEK293 cells Normal Homo sapiens CVCL_0045
SAOS-2 cells Osteosarcoma Homo sapiens CVCL_0548
U2OS cells Osteosarcoma Homo sapiens CVCL_0042
In Vivo Model
Pooled stable cell line was derived from H1299 tet-on ARF cells by transfecting either empty vector or vector overexpressing NRF2. Cells were selected by G418 (1 mg /ml) for 2 weeks and then re-transfected the same vectors again. After additional treatment with or without doxycycline (1.0 mg/ml) for 60 h, 1.0 x 106 of cells were then mixed with Matrigel (BD Biosciences) at 1:1 ratio (volume) and injected subcutaneously into nude mice (NU/NU, Charles River). The mice were fed with the food containing doxycycline hyclate (Harlan, 625 mg/kg) or control food.

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Response regulation ARF (CDKN2A) expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses in Lung adenocarcinomaLung adenocarcinoma.
Experiment 11 Reporting the Ferroptosis-centered Disease Response by This Target [40]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Putative metallothionein MT1DP (MT1DP) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
A total of 6 x 106 A549 cells were subcutaneously injected into the right flank of the athymic BALB/c nude mice (aged 4 weeks, weight 12-16 g; Vital River, Beijing, China). Once tumors reached about 80 mm3, the mice were randomly divided into four groups. Mice were treated with 50 uM/kg erastin by intraperitoneal injection every 2 days for eight times. Tumor size was measured.

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Response regulation Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. In conclusion, MT1DP sensitized non-small cell lung cancer (NSCLC) cells to erastin-induced ferroptosis by regulating the miR-365a-3p/NRF2 signaling pathway.
Experiment 12 Reporting the Ferroptosis-centered Disease Response by This Target [40]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-365a-3p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
A total of 6 x 106 A549 cells were subcutaneously injected into the right flank of the athymic BALB/c nude mice (aged 4 weeks, weight 12-16 g; Vital River, Beijing, China). Once tumors reached about 80 mm3, the mice were randomly divided into four groups. Mice were treated with 50 uM/kg erastin by intraperitoneal injection every 2 days for eight times. Tumor size was measured.

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Response regulation Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. In conclusion, MT1DP sensitized non-small cell lung cancer (NSCLC) cells to erastin-induced ferroptosis by regulating the miR-365a-3p/NRF2 signaling pathway.
Experiment 13 Reporting the Ferroptosis-centered Disease Response by This Target [41]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
Response regulation USP11 is highly expressed in patients with non-small cell lung cancer (NSCLC) and positively correlated with NRF2 expression. Together, USP11 stabilizes NRF2 and is thus an important player in cell proliferation and ferroptosis.
Experiment 14 Reporting the Ferroptosis-centered Disease Response by This Target [42]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator E3 ubiquitin-protein ligase MIB1 (MIB1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell adhesion molecules hsa04514
Notch signaling pathway hsa04330
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
HEK-293T cells Normal Homo sapiens CVCL_0063
Response regulation MIB1 may function as a positive regulator of ferroptosis through targeted degradation of the master antioxidant transcription factor NRF2 and sensitizes lung cancer cells to ferroptosis.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
In total 11 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Cisplatin Investigative
Responsed Regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 ( TNFAIP3) SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Erastin Investigative
Responsed Regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 ( TNFAIP3) SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Tetraarsenic tetrasulfide Investigative
Responsed Regulator RAF proto-oncogene serine/threonine-protein kinase (RAF1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
MAPK signaling pathway hsa04010
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in antiKRAS mutant lung cancer.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [15]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Borneol Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell adhesion molecules hsa04514
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model H460/CisR cells Lung large cell carcinoma Homo sapiens CVCL_C5S1
In Vivo Model
Male Balb/c nude mice (4-week-old) were purchased from SPF (Beijing) biotechnology co., LTD and maintained in the Experimental Animal Research Center of Chengdu University of TCM. After 1 week of adaptable feeding, H460/CDDP cells (5 x 106 cells in 0.1 ml phosphate-buffered saline) were subcutaneously injected into the right dorsal flank to establish tumor model. When the tumor volume grows to 100 mm3, the tumor-bearing mice were randomly divided into the following four treatment groups: a control group (Con, n = 6): intraperitoneal injection of saline once a day; vehicle group (Vehicle, n = 6): intragastric administration of 2% tween and intraperitoneal injection of saline; d-borneol low-dose group (Bor-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day; d-borneol high-dose group (Bor-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day; CDDP group (CDDP, n = 6): intraperitoneal injection of cisplatin (3 mg/kg) every two days; a low-dose combination treatment group (C+B-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days; a high-dose combination treatment group (C+B-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days. We usually first orally gavage d-borneol, and then inject cisplatin intraperitoneally half an hour later. After 14 days treatment, the samples were obtained from the mice for the further experiments.

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Response regulation d-borneol in combination with cisplatin induced ferroptosisviaNCOA4-mediated ferritinophagy and also increased the expression levels of ACSL4, regulated PCBP2 and PRNP to promote the conversion of Fe3+to Fe2+, reduced the activity or expression of antioxidants enzymes (GSH and HO-1), and induced ROS accumulation and thereby promoted ferroptosis. In addition, activation of autophagy inhibited progression of the EMT and increased sensitivity to cisplatin in cisplatin-resistant lung cancer cells.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [44]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Curcumin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell proliferation
Cell autophagy
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
Female C57BL/6 mice (14-18 g) were purchased from SiPeiFu (Beijing) Biotechnology. C57BL/6 mice were subcutaneously injected with a total of 6 x 105 Lewis lung carcinomas (LLC) cells on the left flank. Four days after LLC inoculation, the mice were randomly divided into two groups of five. The vehicle control and curcumin groups were given sodium carboxymethyl cellulose (CMC) or curcumin (100 mg/kg/day) by intraperitoneal injection for 15 days.

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Response regulation Curcumin induced ferroptosis via activating autophagy in non-small-cell lung cancer (NSCLC), which enhanced the therapeutic effect of NSCLC. Meanwhile, the protein level of ACSL4 was higher and the levels of SLC7A11 and GPX4 were lower in curcumin group than that in control group.
Experiment 6 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Sentrin-specific protease 1 (SENP1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 7 Reporting the Ferroptosis-centered Disease Response by This Target [43]
Target for Ferroptosis Driver
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Fatty acid-binding protein, heart (FABP3) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
All athymic nude mice (6-week-old) were purchased from Jiesijie (Shanghai, China). To generate routine cell-derived xenograft (CDX) mouse models, established LUAD cells (initial 5 x 106) were subcutaneously injected into the bilateral dorsal flank of athymic nude mice. To generate H1975/A549 cell-implanted intrapulmonary LUAD mice, athymic nude mice were intrapulmonarily injected with cells (5 x 106) under anesthesia and then intranasally administered adeno-associated virus 5 (AAV5) particles (2 x 1012 viral particles/mL, Genomeditech, Shanghai, China) 3 weeks later. To generate patient-derived xenograft (PDX) mouse models, fresh LUAD tissues with a size of 2-3 mm3 were subcutaneously implanted into athymic nude mice. After successful passage, the PDX mice were used for further studies.

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Response regulation Intracellular cir93FABP3 interactions are critical to upregulate FABP3 to reduce global AA via reactions with taurine. The product of AA and taurine (i.e., NAT) prevents AA incorporation into the plasma membrane, thus further reducing the opportunity for PUFA peroxidation in the membrane. NAT reduces ACSL4, LPCAT3 and PLTP. Exosome and cir93 are critical to desensitize lung adenocarcinoma to ferroptosis.
Experiment 8 Reporting the Ferroptosis-centered Disease Response by This Target [45]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-1290 (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H520 cells Lung squamous cell carcinoma Homo sapiens CVCL_1566
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
Male BALB/c nude mice (3-4 weeks, 16-20 g) were purchased from Vital River Laboratory (Beijing, China) and housed under standard conditions. After acclimatization for one week, mice were randomly divided into two groups (n = 6/group). A549 cells infected with lentivirus circSCN8A (Lv-circSNC8A) or control (Lv-vector) were selected in the presence of puromycin (1 ug/ml). A549 cells (7 x 106) with Lv-circSNC8A or Lv-vector were suspended in 100 uL PBS and respectively injected into each mouse at the right flank.

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Response regulation CircSCN8A represses cell proliferation and metastasis in NSCLC by regulating the miR-1290/ACSL4 axis to induce ferroptosis. Thus, circSCN8A may represent a promising therapeutic target against NSCLC.
Experiment 9 Reporting the Ferroptosis-centered Disease Response by This Target [46]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator NEAT1 (IncRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HBE1 cells Normal Homo sapiens CVCL_0287
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
95D cells Lung giant cell carcinoma Homo sapiens CVCL_7110
Response regulation NEAT1 regulated levels of ACSL4 and proteins related to the ferroptosis and classical apoptosis pathways. And NEAT1 regulates ferroptosis and ferroptosis sensitivity, with the latter depending on ACSL4, suggesting that targeting NEAT1 or ACSL4 may be a viable therapeutic approach to the treatment of non-small-cell lung cancer (NSCLC).
Experiment 10 Reporting the Ferroptosis-centered Disease Response by This Target [45]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator CircSCN8A (circRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H520 cells Lung squamous cell carcinoma Homo sapiens CVCL_1566
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
Male BALB/c nude mice (3-4 weeks, 16-20 g) were purchased from Vital River Laboratory (Beijing, China) and housed under standard conditions. After acclimatization for one week, mice were randomly divided into two groups (n = 6/group). A549 cells infected with lentivirus circSCN8A (Lv-circSNC8A) or control (Lv-vector) were selected in the presence of puromycin (1 ug/ml). A549 cells (7 x 106) with Lv-circSNC8A or Lv-vector were suspended in 100 uL PBS and respectively injected into each mouse at the right flank.

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Response regulation CircSCN8A represses cell proliferation and metastasis in NSCLC by regulating the miR-1290/ACSL4 axis to induce ferroptosis. Thus, circSCN8A may represent a promising therapeutic target against NSCLC.
Experiment 11 Reporting the Ferroptosis-centered Disease Response by This Target [43]
Target for Ferroptosis Driver
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cir93 (circRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
All athymic nude mice (6-week-old) were purchased from Jiesijie (Shanghai, China). To generate routine cell-derived xenograft (CDX) mouse models, established LUAD cells (initial 5 x 106) were subcutaneously injected into the bilateral dorsal flank of athymic nude mice. To generate H1975/A549 cell-implanted intrapulmonary LUAD mice, athymic nude mice were intrapulmonarily injected with cells (5 x 106) under anesthesia and then intranasally administered adeno-associated virus 5 (AAV5) particles (2 x 1012 viral particles/mL, Genomeditech, Shanghai, China) 3 weeks later. To generate patient-derived xenograft (PDX) mouse models, fresh LUAD tissues with a size of 2-3 mm3 were subcutaneously implanted into athymic nude mice. After successful passage, the PDX mice were used for further studies.

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Response regulation Intracellular cir93 FABP3 interactions are critical to upregulate FABP3 to reduce global AA via reactions with taurine. The product of AA and taurine (i.e., NAT) prevents AA incorporation into the plasma membrane, thus further reducing the opportunity for PUFA peroxidation in the membrane. NAT reduces ACSL4, LPCAT3 and PLTP. Exosome and cir93 are critical to desensitize lung adenocarcinoma to ferroptosis.
Ferritin heavy chain (FTH1)
In total 5 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [8]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Curcumenol Investigative
Responsed Regulator H19 (IncRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
HEK-293T cells Normal Homo sapiens CVCL_0063
CCD-19Lu cells Normal Homo sapiens CVCL_2382
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
A subcutaneous tumor-bearing nude mouse model was established by injecting the flank of BALB/c nude mice with 5 x 106 H460 cells. Ten days later, mice were blindly randomized into four groups and intravenously injected with 200 ul ddH2O containing 0.1% CMC-Na and 1% Tween 80, iron chelators DFO (100 mg/kg/day), curcumenol (200 mg/kg/day), and curcumenol combine DFO. Tumor long diameter, short diameter, and body weight were detected every two days after the first drug treatment. The tumor volume calculation formula: (tumor long diameter x tumor short diameter2)/2. Finally, mice were sacrificed. All tumors were collected for immunohistochemical (IHC) staining.

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Response regulation The natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [8]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Curcumenol Investigative
Responsed Regulator hsa-miR-19b-3p (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
HEK-293T cells Normal Homo sapiens CVCL_0063
CCD-19Lu cells Normal Homo sapiens CVCL_2382
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
A subcutaneous tumor-bearing nude mouse model was established by injecting the flank of BALB/c nude mice with 5 x 106 H460 cells. Ten days later, mice were blindly randomized into four groups and intravenously injected with 200 ul ddH2O containing 0.1% CMC-Na and 1% Tween 80, iron chelators DFO (100 mg/kg/day), curcumenol (200 mg/kg/day), and curcumenol combine DFO. Tumor long diameter, short diameter, and body weight were detected every two days after the first drug treatment. The tumor volume calculation formula: (tumor long diameter x tumor short diameter2)/2. Finally, mice were sacrificed. All tumors were collected for immunohistochemical (IHC) staining.

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Response regulation The natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Betulin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRAS mutant non-small-cell lung cancer (NSCLC) cells.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Gefitinib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRAS mutant non-small-cell lung cancer (NSCLC) cells.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [18]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cysteine desulfurase (NFS1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MCF10DCIS cells Normal Homo sapiens CVCL_5552
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
SW900 cells Lung squamous cell carcinoma Homo sapiens CVCL_1731
NCI-H196 cells Lung small cell carcinoma Homo sapiens CVCL_1509
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H2170 cells Lung squamous cell carcinoma Homo sapiens CVCL_1535
NCI-H647 cells Lung adenosquamous carcinoma Homo sapiens CVCL_1574
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
NCI-H838 cells Lung adenocarcinoma Homo sapiens CVCL_1594
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
NCI-H322 cells Lung adenocarcinoma Homo sapiens CVCL_1556
A-498 cells Renal cell carcinoma Homo sapiens CVCL_1056
In Vivo Model
Tumours were initiated in 4-8-week-old female NOD. CB17 Scid/J mice. Orthotopically in the mouse mammary gland, by implantation of 500,000 cells in 25 ul 33% Matrigel into the fourth mouse mammary fat pad; subcutaneously, by injection of 500,000 cells in 100 ul 33% Matrigel into the left or right flank of the mouse; via tail vein by injection of 500,000 cells in 150 ul RPMI into the mouse tail vein; and via intratracheal instillation by instilling 200,000 cells in 50 ul 2 mM EDTA as described. Cancer cells were transduced with viral shRNAs, selected for 3 days with puromycin, and allowed to recover for one day before introduction into mice. For experiments comparing subcutaneous and lung tumour formation, shRNA transduced cells were prepared at the same time and injected on the same day. Animals were imaged by IVIS (Perkin Elmer) 15 min following injection subcutaneously into the neck scruff with XenoLight d-Luciferin (165 mg per kg body weight, Perkin Elmer). Average luminescence was quantified per mouse from equal sized bins covering the mouse thorax. For experiments in which tumour growth was measured upon drug treatment, MDA-MB-231 cells, implanted as described above, were allowed to form palpable tumours (~4 mm diameter) and mice were sorted into treatment groups as described below. PEG-Cyst(e)inase was delivered via intraperitoneal injection at 50 mg per kg body weight every 3 days, SSA was delivered by daily intraperitoneal injection at 250 mg per kg body weight, and BSO was delivered in the drinking water at 20 mM with 5 mg ml-1 sucralose.

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Response regulation NFS1 suppression induced TFRC expression and repressed FTH1 and cytoplasmic aconitase activity. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.
Cystine/glutamate transporter (SLC7A11)
In total 17 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Cisplatin Investigative
Responsed Regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 ( TNFAIP3) SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Erastin Investigative
Responsed Regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 ( TNFAIP3) SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [9]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Nortriptyline hydrochloride Investigative
Responsed Regulator RNA-binding motif, single-stranded-interacting protein 1 (RBMS1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Doxorubicin (Dox)- inducible RBMS1 knockdown stable cells (3 x 106 ) were injected subcutaneously into the abdomen side of 6-week-old BALB/c nude mice (Vital River). Mice were fed either with sucrose water or sucrose water containing 0.1% doxycycline hyclate. H1299 vector, 4 H1299 pLKO.1 RBMS1 and H1299 pLKO.1 RBMS1/SLC7A11 cells (2.5 x 106 ) were injected subcutaneously into the abdomen side of 6-week-old BALB/c nude mice(Vital River). The xenograft tumour formation was monitored using callipers every 3 days.

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Response regulation RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. Nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Tetraarsenic tetrasulfide Investigative
Responsed Regulator RAF proto-oncogene serine/threonine-protein kinase (RAF1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
MAPK signaling pathway hsa04010
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in antiKRAS mutant lung cancer.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [36]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Manoalide Phase 2
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H157 cells Oral cavity Squamous cell carcinoma Homo sapiens CVCL_2458
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
The LSL-KrasG12D mouse model was obtained from the Jackson Laboratory (Sacramento, CA). Adeno-Cre (Genechem, Shanghai, China) was introduced into the trachea of mice at a dose of 1.25 x 1011 PFU in a total volume of 50 uL. Tumor tissues from 12-week post-infection mice were washed with cold PBS, cut into small pieces, and washed with DMEM/F12 (containing 1 x Glutamine, 10 mM HEPES, and antibiotics), digested with collagenase I and IV for 0.5-1 h at 37. After washing twice with DMEM/F12 and centrifugation (500 g, 5 min), the dissociated cells were seeded into growth factor-reduced matrigel (Corning, #356237) at 37 for 30 min.

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Response regulation Manoalide (MA) induces ferroptosis by suppressing the NRF2-SLC7A11 axis and mitochondrial Ca2+overload induced-FTH1 pathways to promote the sensitivity of osimertinib-resistant lung cancer cells to osimertinib.
Experiment 6 Reporting the Ferroptosis-centered Disease Response by This Target [12]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug XAV939 Preclinical
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell proliferation
Cell apoptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
Response regulation The downregulation of the lncRNA MIR503HG induced by XAV939 may serve an important role in suppressing the progression of non-small cell lung cancer via sponging miR1273c, to downregulate its target SOX4. Furthermore, the downregulation of SLC7A11 induced by XAV939 may inhibit NSCLC development via participation in the ferroptosis pathway.
Experiment 7 Reporting the Ferroptosis-centered Disease Response by This Target [27]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Capsaicin Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
Response regulation Capsaicin inhibited the proliferation of A549 and NCI-H23 cells and induced ferroptosis by inactivating SLC7A11/GPX4 signaling. Capsaicin could be used as a potential anticancer agent in the treatment of non-small cell lung cancer.
Experiment 8 Reporting the Ferroptosis-centered Disease Response by This Target [30]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Ginkgetin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
In Vivo Model
Briefly, when tumours on transplanted nude mice reached around 100 mm3, the mice were randomized divided into eight groups: control, ginkgetin, DDP, ginkgetin + DDP, UAMC 3203, ginkgetin + UAMC 3203, DDP + UAMC 3203, ginkgetin + DDP + UAMC 3203. Both DDP (3 mg/kg) and ginkgetin (30 mg/kg) were administered by intraperitoneal injection, with 2 - 3 times per week and once per day, respectively. UAMC 3203 (10 mg/kg) was administered 5 days/week by intraperitoneally injection. Tumour size and body weight were measured 3 times per week. After dosing 31 days, the nude mice were sacrificed, and tumours were removed and weighed.

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Response regulation The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured non-small cell lung cancer (NSCLC) cells.
Experiment 9 Reporting the Ferroptosis-centered Disease Response by This Target [50]
Target for Ferroptosis Suppressor
Responsed Disease Small cell lung cancer [ICD-11: 2C25]
Responsed Drug Sulforaphane Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model H69 cells Normal Homo sapiens CVCL_8121
NCI-H82 cells Lung small cell carcinoma Homo sapiens CVCL_1591
H69AR cells Lung small cell carcinoma Homo sapiens CVCL_3513
Response regulation Sulforaphane (SFN)-induced cell death was mediated via ferroptosis and inhibition of the mRNA and protein expression levels of SLC7A11 in small-cell lung cancer (SCLC) cells. The anticancer effects of SFN may provide novel options for SCLC treatment.
Experiment 10 Reporting the Ferroptosis-centered Disease Response by This Target [51]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator 3'-5' RNA helicase YTHDC2 Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
BEAS-2B cells Normal Homo sapiens CVCL_0168
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H441 cells Lung papillary adenocarcinoma Homo sapiens CVCL_1561
NCI-H1650 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
NCI-H292 cells Lung mucoepidermoid carcinoma Homo sapiens CVCL_0455
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
In Vivo Model
For xenograft experiments, 1.5 x 107 Doxocycline (Dox)-inducible YTHDC2-expressing H1299 cells were subcutaneously injected into 4-6-week-oldathymic nude mice. At day 14 post inoculation, mice were randomly divided into 2 groups for further administrating with or without Dox (30 mg/kg) every other day. Tumors were assessed after sacrificing the mice at day 28 after implantation.

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Response regulation The m6A reader YT521-B homology containing 2 (YTHDC2) has been identified to inhibit lung adenocarcinoma (LUAD) tumorigenesis by suppressing solute carrier 7A11 (SLC7A11)-dependent antioxidant function. YTHDC2 also suppresses SLC3A2 subunit via inhibiting HOXA13-mediated SLC3A2 transcription.
Experiment 11 Reporting the Ferroptosis-centered Disease Response by This Target [52]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Transcription factor SOX-2 (SOX2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model hTCs (Human tumour cells)
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
SW620 cells Colon adenocarcinoma Homo sapiens CVCL_0547
HEK-293T cells Normal Homo sapiens CVCL_0063
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
In Vivo Model
Mice were housed in the SIBCB animal facility under SPF conditions with a 12 hours light/dark cycle at room temperature. For Erastin treatment, we sequentially dissolved Erastin in 5% DMSO, 30% PEG300, 5% Tween80 and ddH2O according to the manufacturers instructions, it should be noted that the solvent needed to be added from left to right, after the dissolution was completely clear, added the next reagent, 40 mg/kg Erastin was intraperitoneal injected, every other day for 2 weeks. For IKE treatment, 50 mg/kg IKE was intraperitoneal injected, once a day for 2 weeks.

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Response regulation Tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.
Experiment 12 Reporting the Ferroptosis-centered Disease Response by This Target [53]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-27a-3p (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Response regulation MiR-27a-3p, was an essential modulator of ferroptosisviadirectly targeting SLC7A11 in non-small cell lung cancer cells. Overexpressing miR-27a-3p led to SLC7A11 suppressionviadirectly binding to its 3'-UTR, followed by the reduction of erastin-caused ferroptosis.
Experiment 13 Reporting the Ferroptosis-centered Disease Response by This Target [54]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator CircFOXP1 (circRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model HT29 cells Colon cancer Mus musculus CVCL_A8EZ
In Vivo Model
SCID/nude mice (6 weeks old) were ordered from Laboratory Animal Center of Chinese Academy of Sciences (Beijing, China). HT29 cells were co-transfected with sh-circFOXP1 and pCMV-SLC7A11 or empty vector. Cells were digested, 5 x 106 cells were mixed with Matrigel (Corning) and subcutaneously injected into mice. The width and length of tumor were measured at indicated time, and the tumor size was calculated by the formula: 0.5 x length x width2. Mice were then succumbed to death, the tumors were isolated, weighted, and made into paraffin-embedded slices (5-um). The slices were stained with anti-KI67 antibody (Santa Cruz Biotechnology) and subsequent HRP-labeled secondary antibody and captured in a microscope (Leica Microsystems).

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Response regulation Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells.
Experiment 14 Reporting the Ferroptosis-centered Disease Response by This Target [54]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator hsa-miR-520a-5p (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model HT29 cells Colon cancer Mus musculus CVCL_A8EZ
In Vivo Model
SCID/nude mice (6 weeks old) were ordered from Laboratory Animal Center of Chinese Academy of Sciences (Beijing, China). HT29 cells were co-transfected with sh-circFOXP1 and pCMV-SLC7A11 or empty vector. Cells were digested, 5 x 106 cells were mixed with Matrigel (Corning) and subcutaneously injected into mice. The width and length of tumor were measured at indicated time, and the tumor size was calculated by the formula: 0.5 x length x width2. Mice were then succumbed to death, the tumors were isolated, weighted, and made into paraffin-embedded slices (5-um). The slices were stained with anti-KI67 antibody (Santa Cruz Biotechnology) and subsequent HRP-labeled secondary antibody and captured in a microscope (Leica Microsystems).

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Response regulation Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells.
Experiment 15 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Sentrin-specific protease 1 (SENP1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. There were six mice in each group. A total of 2 x 106 cells were seeded subcutaneously into 6-week-old BALB/ C-Nu Male mice. Tumor width (W) and length (L) at different experimental time points were measured with calipers, and tumor growth was monitored.

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Response regulation SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.
Experiment 16 Reporting the Ferroptosis-centered Disease Response by This Target [55]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Uc.339 (IncRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
Cell proliferation
Cell metastasis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
16HBE14o- cells Normal Homo sapiens CVCL_0112
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
6-8 weeks mice were divided into 4 groups randomly. Mice were injected with 2.5 x 105 wild type LLC cells, Uc.339 OE-LLC cells, with or without miR-339 inhibitors, respectively, through the lateral tail vain. The mice were killed after 4 weeks by carbon dioxide asphyxiation followed by cervical dislocation to ensure death. The lungs were removed, rinsed with PBS, and the number of metastatic foci on the lung surface was counted. The pulmonary lobes were subsequently kept in 4% paraformaldehyde for later paraffin embedding and hematoxylin and eosin staining.

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Response regulation LncRNA Uc.339 competitively binds to pri-miR-339 and inhibits the production of mature miR-339. At the same time, it is the first to clarify the reason for the negative correlation between miR-339 and SLC7A11 expression in lung cancer, and for the first verification that the inhibition of miR-339 led to increased expression of SLC7A11 and weakens ferroptosis, which constituted an important carcinogenesis mechanism for lung adenocarcinoma metastasis.
Experiment 17 Reporting the Ferroptosis-centered Disease Response by This Target [55]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator hsa-miR-339-3p (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
Cell proliferation
Cell metastasis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
16HBE14o- cells Normal Homo sapiens CVCL_0112
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
6-8 weeks mice were divided into 4 groups randomly. Mice were injected with 2.5 x 105 wild type LLC cells, Uc.339 OE-LLC cells, with or without miR-339 inhibitors, respectively, through the lateral tail vain. The mice were killed after 4 weeks by carbon dioxide asphyxiation followed by cervical dislocation to ensure death. The lungs were removed, rinsed with PBS, and the number of metastatic foci on the lung surface was counted. The pulmonary lobes were subsequently kept in 4% paraformaldehyde for later paraffin embedding and hematoxylin and eosin staining.

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Response regulation LncRNA Uc.339 competitively binds to pri-miR-339 and inhibits the production of mature miR-339. At the same time, it is the first to clarify the reason for the negative correlation between miR-339 and SLC7A11 expression in lung cancer, and for the first verification that the inhibition of miR-339 led to increased expression of SLC7A11 and weakens ferroptosis, which constituted an important carcinogenesis mechanism for lung adenocarcinoma metastasis.
Unspecific Target
In total 41 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [10]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Levobupivacaine Approved
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
A427 cells Lung carcinoma Homo sapiens CVCL_1055
In Vivo Model
Balb/c nude mice (n= 5, 4-week-old, male) were applied to detect the impact of levobupivacaine on tumor growth. Mice subcutaneously injected with 1 x 107 A549 cells were treated with levobupivacaine (40 umol/Kg) or equal volume saline. The tumor volume was remarked every 5 days and finished at 30 days after injection, followed by the analysis of volume (length (width/2)2) and weight.

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Response regulation Levobupivacaine could inhibit the proliferation and induce the apoptosis of non-small cell lung cancer (NSCLC) cells. Levobupivacaine was able to attenuate the invasion and migration in the cells. The treatment of levobupivacaine remarkably increased the levels of ROS, iron, and Fe2+ in NSCLC cells. Mechanically, levobupivacaine up-regulated the expression of p53 and induced ferroptosis by regulating p53 in NSCLC cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [11]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Gingerol Investigative
Responsed Regulator Ubiquitin carboxyl-terminal hydrolase 14 (USP14) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
BALB/cNude (6-8 weeks of age) mice were purchased from Hangzhou Ziyuan Experimental Animal Technology Co. Ltd. (SYXK-20180049) for this study. The mice were housed under specific pathogen-free conditions at 23 and given free access to food and water. The left flank of mice was subcutaneously inoculated with A549 tumor-cell suspension (5 x 106 cells/100uL) to prepare A549 tumor xenografts. Three days after tumor cell inoculation, the mice were divided into three groups (n = 8): Con group (control group, no treatment), L-Gin group (0.25 mg/kg/day 6-Gingerol), H-Gin group (0.5 mg/kg/day 6-Gingerol), which were administered orally daily until the end of the experiments. Mice were killed when their minor axis of tumors were longer than 20 mm.

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Response regulation 6-Gingerol inhibits lung cancer cell growth via suppression of USP14 expression and its downstream regulation of autophagy-dependent ferroptosis, revealing the function and efficacy of 6-Gingerol as a therapeutic compound in A549 and its possible mechanism of action.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [12]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug XAV939 Preclinical
Responsed Regulator Transcription factor SOX-4 (SOX4) Suppressor
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell proliferation
Cell apoptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
Response regulation The downregulation of the lncRNA MIR503HG induced by XAV939 may serve an important role in suppressing the progression of non-small cell lung cancer via sponging miR1273c, to downregulate its target SOX4. Furthermore, the downregulation of SLC7A11 induced by XAV939 may inhibit NSCLC development via participation in the ferroptosis pathway.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [12]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug XAV939 Preclinical
Responsed Regulator hsa-miR-1273c (miRNA) Driver
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell proliferation
Cell apoptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
Response regulation The downregulation of the lncRNA MIR503HG induced by XAV939 may serve an important role in suppressing the progression of non-small cell lung cancer via sponging miR1273c, to downregulate its target SOX4. Furthermore, the downregulation of SLC7A11 induced by XAV939 may inhibit NSCLC development via participation in the ferroptosis pathway.
Experiment 5 Reporting the Ferroptosis-centered Disease Response by This Target [12]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug XAV939 Preclinical
Responsed Regulator MIR503HG (IncRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell proliferation
Cell apoptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
Response regulation The downregulation of the lncRNA MIR503HG induced by XAV939 may serve an important role in suppressing the progression of non-small cell lung cancer via sponging miR1273c, to downregulate its target SOX4. Furthermore, the downregulation of SLC7A11 induced by XAV939 may inhibit NSCLC development via participation in the ferroptosis pathway.
Experiment 6 Reporting the Ferroptosis-centered Disease Response by This Target [13]
Responsed Disease Lung large cell carcinoma [ICD-11: 2C25]
Responsed Drug 1,1-(Decane-1,10-diyl)bis(5-fluoroindoline-2,3-dione) Investigative
Responsed Regulator Parkinson disease protein 7 (PARK7) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
HCC1937 cells Breast ductal carcinoma Homo sapiens CVCL_0290
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
RCC4 cells Clear cell renal cell carcinoma Homo sapiens CVCL_0498
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Tumors were established by injecting 200 uL of H1299 cell suspensions (2 x 106) into BALB/c female athymic nude mice (5 weeks, National Rodent Laboratory Animal Resource, Shanghai, China). When the tumor volume reached an average size of 80 mm3, tumor-bearing mice were subsequently randomly divided into three groups (n = 7 for each group). STK or DM10 was intratumorally administered as a single agent in mouse tumors at a dose of 30 or 15 mg/kg only once.

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Response regulation The PARK7 gene (encode DJ-1 protein) was first discovered as an oncogene and later found to be a causative gene for autosomal recessive early onset Parkinson's disease. 1,1-(Decane-1,10-diyl)bis(5-fluoroindoline-2,3-dione) (DM10) is identified as a potent inhibitor targeting DJ-1 homodimer with the potential as sensitizing agent for other anticancer drugs.
Experiment 7 Reporting the Ferroptosis-centered Disease Response by This Target [14]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25]
Responsed Drug 11-hydroxy-ent-16-kaurene-15-one Investigative
Responsed Regulator Peroxiredoxin-1 (PRDX1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
HBE1 cells Normal Homo sapiens CVCL_0287
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
HUVECs (Human umbilical vein endothelial cells)
In Vivo Model
Thirty male athymic (Balb/c-nu) mice (4-week-old) were purchased from the SPF (Beijing) biotechnology (Beijing, China) and allowed to acclimatize for 1 week. A549/CDDP cells (5 x 106 cells) were injected subcutaneously into the right anterior flanks of the mice. Two weeks after the injection of cells, when the tumors became palpable (around 100 mm3), mice were randomly divided into four groups (n = 6 per group). Tumor-bearing mice were received equal amount of solvent, CDDP (4 mg/kg) or compound 23 (10 mg/kg) or combination CDDP and 23 were injected via intraperitoneal injection. Administration was performed every 3 days for 30 days.

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Response regulation 11-hydroxy-ent-16-kaurene-15-one possessed strong inhibitory activity against several cancer cell lines. Moreover, compound 23 induced both apoptosis and ferroptosis through increasing cellular ROS levels in HepG2 cells. ROS accumulation induced by compound 23 was caused by inhibition of antioxidant systems through targeting peroxiredoxin I (Prdx I) and depletion of GSH in lung adenocarcinoma cells.
Experiment 8 Reporting the Ferroptosis-centered Disease Response by This Target [14]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25]
Responsed Drug 11-hydroxy-ent-16-kaurene-15-one Investigative
Responsed Regulator Peroxiredoxin-2 (PRDX2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
HBE1 cells Normal Homo sapiens CVCL_0287
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
HUVECs (Human umbilical vein endothelial cells)
In Vivo Model
Thirty male athymic (Balb/c-nu) mice (4-week-old) were purchased from the SPF (Beijing) biotechnology (Beijing, China) and allowed to acclimatize for 1 week. A549/CDDP cells (5 x 106 cells) were injected subcutaneously into the right anterior flanks of the mice. Two weeks after the injection of cells, when the tumors became palpable (around 100 mm3), mice were randomly divided into four groups (n = 6 per group). Tumor-bearing mice were received equal amount of solvent, CDDP (4 mg/kg) or compound 23 (10 mg/kg) or combination CDDP and 23 were injected via intraperitoneal injection. Administration was performed every 3 days for 30 days.

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Response regulation 11-hydroxy-ent-16-kaurene-15-one possessed strong inhibitory activity against several cancer cell lines. Moreover, compound 23 induced both apoptosis and ferroptosis through increasing cellular ROS levels in HepG2 cells. ROS accumulation induced by compound 23 was caused by inhibition of antioxidant systems through targeting peroxiredoxin II (Prdx II) and depletion of GSH in lung adenocarcinoma cells.
Experiment 9 Reporting the Ferroptosis-centered Disease Response by This Target [15]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Borneol Investigative
Responsed Regulator Poly(rC)-binding protein 2 (PCBP2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell adhesion molecules hsa04514
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model H460/CisR cells Lung large cell carcinoma Homo sapiens CVCL_C5S1
In Vivo Model
Male Balb/c nude mice (4-week-old) were purchased from SPF (Beijing) biotechnology co., LTD and maintained in the Experimental Animal Research Center of Chengdu University of TCM. After 1 week of adaptable feeding, H460/CDDP cells (5 x 106 cells in 0.1 ml phosphate-buffered saline) were subcutaneously injected into the right dorsal flank to establish tumor model. When the tumor volume grows to 100 mm3, the tumor-bearing mice were randomly divided into the following four treatment groups: a control group (Con, n = 6): intraperitoneal injection of saline once a day; vehicle group (Vehicle, n = 6): intragastric administration of 2% tween and intraperitoneal injection of saline; d-borneol low-dose group (Bor-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day; d-borneol high-dose group (Bor-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day; CDDP group (CDDP, n = 6): intraperitoneal injection of cisplatin (3 mg/kg) every two days; a low-dose combination treatment group (C+B-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days; a high-dose combination treatment group (C+B-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days. We usually first orally gavage d-borneol, and then inject cisplatin intraperitoneally half an hour later. After 14 days treatment, the samples were obtained from the mice for the further experiments.

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Response regulation d-borneol in combination with cisplatin induced ferroptosisviaNCOA4-mediated ferritinophagy and also increased the expression levels of ACSL4, regulated PCBP2 and PRNP to promote the conversion of Fe3+to Fe2+, reduced the activity or expression of antioxidants enzymes (GSH and HO-1), and induced ROS accumulation and thereby promoted ferroptosis. In addition, activation of autophagy inhibited progression of the EMT and increased sensitivity to cisplatin in cisplatin-resistant lung cancer cells.
Experiment 10 Reporting the Ferroptosis-centered Disease Response by This Target [15]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Borneol Investigative
Responsed Regulator Major prion protein (PRNP) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell adhesion molecules hsa04514
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model H460/CisR cells Lung large cell carcinoma Homo sapiens CVCL_C5S1
In Vivo Model
Male Balb/c nude mice (4-week-old) were purchased from SPF (Beijing) biotechnology co., LTD and maintained in the Experimental Animal Research Center of Chengdu University of TCM. After 1 week of adaptable feeding, H460/CDDP cells (5 x 106 cells in 0.1 ml phosphate-buffered saline) were subcutaneously injected into the right dorsal flank to establish tumor model. When the tumor volume grows to 100 mm3, the tumor-bearing mice were randomly divided into the following four treatment groups: a control group (Con, n = 6): intraperitoneal injection of saline once a day; vehicle group (Vehicle, n = 6): intragastric administration of 2% tween and intraperitoneal injection of saline; d-borneol low-dose group (Bor-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day; d-borneol high-dose group (Bor-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day; CDDP group (CDDP, n = 6): intraperitoneal injection of cisplatin (3 mg/kg) every two days; a low-dose combination treatment group (C+B-L, n = 6): intragastric administration of d-borneol (30 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days; a high-dose combination treatment group (C+B-H, n = 6): intragastric administration of d-borneol (60 mg/kg) once a day and intraperitoneal injection of cisplatin (3 mg/kg) every two days. We usually first orally gavage d-borneol, and then inject cisplatin intraperitoneally half an hour later. After 14 days treatment, the samples were obtained from the mice for the further experiments.

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Response regulation d-borneol in combination with cisplatin induced ferroptosisvia NCOA4-mediated ferritinophagy and also increased the expression levels of ACSL4, regulated PCBP2 and PRNP to promote the conversion of Fe3+ to Fe2+, reduced the activity or expression of antioxidants enzymes (GSH and HO-1), and induced ROS accumulation and thereby promoted ferroptosis. In addition, activation of autophagy inhibited progression of the EMT and increased sensitivity to cisplatin in cisplatin-resistant lung cancer cells.
Experiment 11 Reporting the Ferroptosis-centered Disease Response by This Target [16]
Responsed Disease Lung small cell carcinoma [ICD-11: 2C25]
Responsed Drug Oxyfedrine Investigative
Responsed Regulator Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model DMS114 cells Lung small cell carcinoma Homo sapiens CVCL_1174
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
SBC3 cells Small cell lung cancer Homo sapiens CVCL_1678
HSC-2 cells Oral cavity squamous cell carcinoma Homo sapiens CVCL_1287
HSC-3 cells Oral squamous cell carcinoma Homo sapiens CVCL_1288
HSC-4 cells Cervical lymph node Homo sapiens CVCL_1289
OSC-19 cells Tongue squamous cell carcinoma Homo sapiens CVCL_3086
SCC-25 cells Squamous carcinoma Homo sapiens CVCL_1682
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Response regulation Combined treatment with oxyfedrine (OXY) and sulfasalazine (SSZ) was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. And the constitutive activation of Nrf2 results in high expression of xCT and ALDH3A1, and Nrf2 depletion sensitizes Nrf2 overexpressing cancer, such as lung small cell carcinoma, cells to combination therapy with OXY and SSZ.
Experiment 12 Reporting the Ferroptosis-centered Disease Response by This Target [17]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Drug Tectoridin Investigative
Responsed Regulator Serine/threonine-protein kinase PLK1 (PLK1) Driver
Pathway Response Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Response regulation Tectoridin synergized with PLK1 inhibitor to suppress autophagy and ferroptosis but promoted caspase-3-mediated apoptosis in A549 (Lung adenocarcinoma) cells. Our findings highlight a potential drug target and the combination therapy strategy of PLK1 inhibitor and tectoridin for LUAD patients. In vitro experiments, we confirmed that tectoridin could inhibit the expression of PLK1.
Experiment 13 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Tetraarsenic tetrasulfide Investigative
Responsed Regulator GTPase KRas (KRAS) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
MAPK signaling pathway hsa04010
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model NCI-H23 cells Lung adenocarcinoma Homo sapiens CVCL_1547
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
Response regulation Realgar-induced ferroptosis may be mediated via KRAS/Raf/MAPK. Realgar may be targeted to regulate Raf kinase, thereby further regulating the downstream JNK/ERK signaling cascade to suppress KRAS cells and exert an anticancer activity. In conclusion, realgar may induce ferroptosis by regulating the Raf, and hence plays a role in antiKRAS mutant lung cancer.
Experiment 14 Reporting the Ferroptosis-centered Disease Response by This Target [57]
Responsed Disease Non-small cell lung carcinoma [ICD-11: 2C25]
Responsed Drug BMS536924 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Response regulation BMS536924, a dual inhibitor of insulin-like growth and insulin receptors, is a potent inhibitor of ferroptosis in non-small cell lung carcinoma.
Experiment 15 Reporting the Ferroptosis-centered Disease Response by This Target [58]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Dynasore Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H441 cells Lung papillary adenocarcinoma Homo sapiens CVCL_1561
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
NCI-H727 cells Lung carcinoid tumor Homo sapiens CVCL_1584
NCI-H520 cells Lung squamous cell carcinoma Homo sapiens CVCL_1566
H332m (Human non-small cell lung cancer cells)
NCI-H82 cells Lung small cell carcinoma Homo sapiens CVCL_1591
Response regulation Dynasore can function as a highly active inhibitor of ROS-driven types of cell death via combined modulation of the iron pool and inhibition of general ROS by simultaneously blocking two routes required for ROS and lipid-ROS driven cell death in lung cancer, respectively.
Experiment 16 Reporting the Ferroptosis-centered Disease Response by This Target [59]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Drug Erianin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
H460-luc cells (2 x 106 cells in 0.1 ml phosphate-buffered saline) were subcutaneously injected into the right dorsal flank of 6-week-old female BALB/c nude mice; for the orthotopic xenograft lung tumor mouse model, a volume of 100 ul of cell suspension was injected into the right side of the lung. Tumor volume was assessed every 2 days.

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Response regulation Erianin could inhibit cell proliferation, promote G2/M-phase arrest, trigger ferroptosis, and suppress migration in lung cancer cells.
Experiment 17 Reporting the Ferroptosis-centered Disease Response by This Target [60]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator DNA replication complex GINS protein SLD5 (GINS4) Suppressor
Pathway Response Cell adhesion molecules hsa04514
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The 4-wk-old female nude mice used in this study were purchased from Hunan SJA Laboratory Animal Co., Ltd (Changsha). Then, 2 x 106 GINS4 WT or KO A549 cells were injected s.c. into nude mice without matrigel. Tumor size was measured every 2 d with a caliper, and volume of tumor was calculated with the formula: L x W2 x 0.5, for L represents the longest diameter and W means the shortest diameter. Then, 2 x 106 p53 WT and KO A549 cells with shCon or shGINS4 overexpressing were injected s.c. into nude mice without matrigel. When tumors reached 60 to 100 mm3, p53 WT with shGINS4 mice were treated with ferrostatin-1 (S7243, Selleckchem) (20 mg/kg) in 2% DMSO, 50% PEG300, 5% Tween80, and 43% water by daily intraperitoneal injection. Tumors were measured three times a week. Mice were sacrificed and tumors were collected finally. Tumor tissue was made into a single-cell suspension for lipid ROS assay using Tumor Dissociation Kit (Miltenyi Biotec).

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Response regulation GINS4 is a potential oncogene in lung adenocarcinoma (LUAD) that functions to destabilize p53 and then inhibits ferroptosis, providing a potential therapeutic target for LUAD.
Experiment 18 Reporting the Ferroptosis-centered Disease Response by This Target [61]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator LINC00551 (IncRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 106 indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed.

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Response regulation LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.
Experiment 19 Reporting the Ferroptosis-centered Disease Response by This Target [62]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25]
Responsed Regulator Calcium uptake protein 1, mitochondrial (MICU1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Thermogenesis hsa04714
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HEK293A cells Normal Homo sapiens CVCL_6910
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Response regulation MICU1 as a key regulator for lipid peroxidation and subsequent ferroptosis under cold stress, suggesting that MICU1 can be a potential target for preventing lung adenocarcinoma cell death in organ preservation.
Experiment 20 Reporting the Ferroptosis-centered Disease Response by This Target [63]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator LINC00472 (IncRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
HBE1 cells Normal Homo sapiens CVCL_0287
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
95C cells Lung giant cell carcinoma Homo sapiens CVCL_7109
95D cells Lung giant cell carcinoma Homo sapiens CVCL_7110
In Vivo Model
SCID mice (Hunan SJA Laboratory Animal Co. Ltd.) were injected with the indicated cells in the mammary fat pad (10 mice/group). Injected mice were imaged from both the dorsal and ventral sides every three days.

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Response regulation P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis in lung cancer cell lines.
Experiment 21 Reporting the Ferroptosis-centered Disease Response by This Target [64]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Ribonucleoside-diphosphate reductase subunit M2 (RRM2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell infiltration
In Vitro Model LL/2 (LLC1) cells Lung cancer Mus musculus CVCL_4358
hBMDMs (Human bone marrow-derived macrophages)
In Vivo Model
LLC cells were cultured to prepare a single-cell suspension in PBS, and then 5 x 10^6 LLC cells were injected subcutaneously into C57/B6 male mice (Shanghai Slac Laboratory Animal Co. LTD, China) aged 8 weeks. Every group of mice consisted of 6 randomly assigned mice. When the tumor size was visible, the tumor size was measured once every three days until it reached 1000 mm3.

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Response regulation Combined with lung adenocarcinoma tissue samples and mouse trials, RRM2 was found to influence lung cancer progression and affect tumor immune cell infiltration. RRM2 inhibition effectively promoted M1 macrophage polarization and suppressed M2 macrophage polarization in vitro and in vivo.
Experiment 22 Reporting the Ferroptosis-centered Disease Response by This Target [65]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Aldo-keto reductase family 1 member C1 (AKR1C1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
NCI-H292 cells Lung mucoepidermoid carcinoma Homo sapiens CVCL_0455
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Mice in the + dox groups were fed a diet of doxycycline chow 3 days prior to injecting cells and throughout the remainder of the experiment. Mice in the -dox group were fed a diet of amoxicillin chow to avoid skin rash. Subcutaneous flank tumors were generated by injecting 5E6 A549 or 2E6 H460 confluent cells (n = 5 per group) suspended in 50% Matrigel into the right flank.

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Response regulation Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis.
Experiment 23 Reporting the Ferroptosis-centered Disease Response by This Target [66]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Kinesin-like protein KIF20A (KIF20A) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
16HBE14o- cells Normal Homo sapiens CVCL_0112
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Response regulation GEM and the ferroptosis inducer IKE synergistically inhibited the proliferation of lung adenocarcinoma (LUAD) cells. Targeting the FRG KIF20A can enhance ferroptosis and modulate the combination of GEM and IKE, which might serve as a therapeutic target in LUAD.
Experiment 24 Reporting the Ferroptosis-centered Disease Response by This Target [60]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
Pathway Response Cell adhesion molecules hsa04514
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The 4-wk-old female nude mice used in this study were purchased from Hunan SJA Laboratory Animal Co., Ltd (Changsha). Then, 2 x 106 GINS4 WT or KO A549 cells were injected s.c. into nude mice without matrigel. Tumor size was measured every 2 d with a caliper, and volume of tumor was calculated with the formula: L x W2 x 0.5, for L represents the longest diameter and W means the shortest diameter. Then, 2 x 106 p53 WT and KO A549 cells with shCon or shGINS4 overexpressing were injected s.c. into nude mice without matrigel. When tumors reached 60 to 100 mm3, p53 WT with shGINS4 mice were treated with ferrostatin-1 (S7243, Selleckchem) (20 mg/kg) in 2% DMSO, 50% PEG300, 5% Tween80, and 43% water by daily intraperitoneal injection. Tumors were measured three times a week. Mice were sacrificed and tumors were collected finally. Tumor tissue was made into a single-cell suspension for lipid ROS assay using Tumor Dissociation Kit (Miltenyi Biotec).

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Response regulation GINS4 is a potential oncogene in lung adenocarcinoma (LUAD) that functions to destabilize p53 and then inhibits ferroptosis, providing a potential therapeutic target for LUAD.
Experiment 25 Reporting the Ferroptosis-centered Disease Response by This Target [67]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Lysine-specific histone demethylase 1A (KDM1A) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H157 cells Oral cavity Squamous cell carcinoma Homo sapiens CVCL_2458
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
Response regulation Knockdown of KDM1A inhibited the level of c-Myc and increased the concentration of malondialdehyde (MDA) and irons in human lung cancer cells H1299 and A549. Downregulation of c-Myc could facilitate KDM1A knockdown-mediated ferroptosis.
Experiment 26 Reporting the Ferroptosis-centered Disease Response by This Target [68]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator LINC01572 (IncRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H2009 cells Lung adenocarcinoma Homo sapiens CVCL_1514
HBE1 cells Normal Homo sapiens CVCL_0287
Response regulation Knockdown of LINC01572 significantly inhibited cell viability and induced ferroptosis in lung adenocarcinoma (LUAD) cell lines.
Experiment 27 Reporting the Ferroptosis-centered Disease Response by This Target [67]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Myc proto-oncogene protein (MYC) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H157 cells Oral cavity Squamous cell carcinoma Homo sapiens CVCL_2458
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
Response regulation Knockdown of KDM1A inhibited the level of c-Myc and increased the concentration of malondialdehyde (MDA) and irons in human lung cancer. cells H1299 and A549. Downregulation of c-Myc could facilitate KDM1A knockdown-mediated ferroptosis.
Experiment 28 Reporting the Ferroptosis-centered Disease Response by This Target [61]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator hsa-miR-4328 (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 106 indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed.

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Response regulation LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.
Experiment 29 Reporting the Ferroptosis-centered Disease Response by This Target [61]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator DNA damage-inducible transcript 4 protein (DDIT4) Driver
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 106 indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed.

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Response regulation LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.
Experiment 30 Reporting the Ferroptosis-centered Disease Response by This Target [61]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Serine/threonine-protein kinase mTOR (MTOR) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 106 indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed.

    Click to Show/Hide
Response regulation LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.
Experiment 31 Reporting the Ferroptosis-centered Disease Response by This Target [20]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Acyl-CoA 6-desaturase (FADS2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model MRC-5 cells Normal Homo sapiens CVCL_0440
HBE1 cells Normal Homo sapiens CVCL_0287
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
95C cells Lung giant cell carcinoma Homo sapiens CVCL_7109
95D cells Lung giant cell carcinoma Homo sapiens CVCL_7110
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
SCID Mice (Hunan SJA Laboratory Animal Co.Ltd.) were injected with A549 (1 x 106 cells/mouse) or H358 (2 x 106 cells/mouse) cells via mammary fat pad (10 mice/group). Mice with A549 or H358 cells were imaged from dorsal and ventral views every three days.

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Response regulation LSH (HELLS) is involved in ferroptosis and is a potential therapeutic target in cancer because of its crucial role in ferroptosis. LSH functioned as an oncogene in lung cancer in vitro and in vivo. And LSH promotes the lipid metabolic genes, including SCD1 and FADS2.
Experiment 32 Reporting the Ferroptosis-centered Disease Response by This Target [69]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator ELAV-like protein 1 (ELAVL1) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
Response regulation LSH induces ELAVL1 expression through the inactivation of p53 and ELAVL1 enhances LINC00336 levels through transcriptional regulation by interacting with LINC00336. Then, LINC00336 absorbs MIR6852 as a ceRNA, which increases the mRNA level of CBS, stimulating cell proliferation, colony formation, and tumor formation, and inhibiting ferroptosis in lung cancer.
Experiment 33 Reporting the Ferroptosis-centered Disease Response by This Target [69]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator LINC00336 (IncRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
Response regulation LSH induces ELAVL1 expression through the inactivation of p53 and ELAVL1 enhances LINC00336 levels through transcriptional regulation by interacting with LINC00336. Then, LINC00336 absorbs MIR6852 as a ceRNA, which increases the mRNA level of CBS, stimulating cell proliferation, colony formation, and tumor formation, and inhibiting ferroptosis in lung cancer.
Experiment 34 Reporting the Ferroptosis-centered Disease Response by This Target [69]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator hsa-mir-6852 (Precursor RNA) Driver
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
Response regulation LSH induces ELAVL1 expression through the inactivation of p53 and ELAVL1 enhances LINC00336 levels through transcriptional regulation by interacting with LINC00336. Then, LINC00336 absorbs MIR6852 as a ceRNA, which increases the mRNA level of CBS, stimulating cell proliferation, colony formation, and tumor formation, and inhibiting ferroptosis in lung cancer.
Experiment 35 Reporting the Ferroptosis-centered Disease Response by This Target [69]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Cystathionine beta-synthase (CBS) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
Response regulation LSH induces ELAVL1 expression through the inactivation of p53 and ELAVL1 enhances LINC00336 levels through transcriptional regulation by interacting with LINC00336. Then, LINC00336 absorbs MIR6852 as a ceRNA, which increases the mRNA level of CBS, stimulating cell proliferation, colony formation, and tumor formation, and inhibiting ferroptosis in lung cancer.
Experiment 36 Reporting the Ferroptosis-centered Disease Response by This Target [63]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
Pathway Response Fatty acid metabolism hsa01212
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
HBE1 cells Normal Homo sapiens CVCL_0287
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
95C cells Lung giant cell carcinoma Homo sapiens CVCL_7109
95D cells Lung giant cell carcinoma Homo sapiens CVCL_7110
In Vivo Model
SCID mice (Hunan SJA Laboratory Animal Co. Ltd.) were injected with the indicated cells in the mammary fat pad (10 mice/group). Injected mice were imaged from both the dorsal and ventral sides every three days.

    Click to Show/Hide
Response regulation P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis in lung cancer cell lines.
Experiment 37 Reporting the Ferroptosis-centered Disease Response by This Target [70]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator hsa-miR-101-3p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
hTCs (Human tumour cells)
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
GLC-82 cells Endocervical adenocarcinoma Homo sapiens CVCL_3371
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
BALB/c mice (male, 6 weeks old, 20-22 g) were obtained from Vital River Laboratories (Beijing, China). Immunodeficient mice were randomly divided into groups (n = 6 per group). A549 cells (1 x 106) were injected subcutaneously into the dorsal left flank of nude mice. In each group, mice (20-25 g) were administered 100 uL of the nanomedicine working solution through the tail vein, once every 3 days.

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Response regulation The expression level of miR-101-3p negatively correlated with clinical tumour size and TNM stage. miR-101-3p restores ferroptosis in lung cancer cells by directly targeting TBLR1, which in turn promotes apoptosis and inhibits proliferation.
Experiment 38 Reporting the Ferroptosis-centered Disease Response by This Target [70]
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
hTCs (Human tumour cells)
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
GLC-82 cells Endocervical adenocarcinoma Homo sapiens CVCL_3371
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
In Vivo Model
BALB/c mice (male, 6 weeks old, 20-22 g) were obtained from Vital River Laboratories (Beijing, China). Immunodeficient mice were randomly divided into groups (n = 6 per group). A549 cells (1 x 106) were injected subcutaneously into the dorsal left flank of nude mice. In each group, mice (20-25 g) were administered 100 uL of the nanomedicine working solution through the tail vein, once every 3 days.

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Response regulation The expression level of miR-101-3p negatively correlated with clinical tumour size and TNM stage. miR-101-3p restores ferroptosis in lung cancer cells by directly targeting TBLR1, which in turn promotes apoptosis and inhibits proliferation.
Experiment 39 Reporting the Ferroptosis-centered Disease Response by This Target [71]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Aldo-keto reductase family 1 member C1 (AKR1C1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
BEAS-2B cells Normal Homo sapiens CVCL_0168
Response regulation The expression of AKR1C1 was upregulated in non-small cell lung cancer (NSCLC) cell lines, and silencing AKR1C1 can inhibit the proliferation and migration of NSCLC cells and promote the occurrence of ferroptosis.
Experiment 40 Reporting the Ferroptosis-centered Disease Response by This Target [72]
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Serine/threonine-protein kinase STK11 (STK11) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
In Vitro Model mEFs (Mouse embryonic fibroblasts)
Response regulation The main upstream kinase responsible for the activation of AMPK in response to energy stress is LKB1 (STK11), LKB1 is a negative regulator of ferroptosis and LKB1 status might be useful as a biomarker to predict non-small cell lung carcinoma responsiveness to the induction of ferroptosis.
Experiment 41 Reporting the Ferroptosis-centered Disease Response by This Target [56]
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator 6-phosphogluconate dehydrogenase, decarboxylating (PGD) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell infiltration
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
Response regulation The study found GSEC, CISD1, ATP5MC3, and PGD to be upregulated, with miRNA-101-3p downregulated, in the setting of lung adenocarcinoma (LUAD). Immunohistochemical analysis revealed CISD1, ATP5MC3, and PGD overexpression in LUAD tissue samples; CISD1 knockdown was noted to significantly inhibit LUAD proliferation and migration.
Transferrin receptor protein 1 (TFRC)
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [18]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cysteine desulfurase (NFS1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MCF10DCIS cells Normal Homo sapiens CVCL_5552
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
SW900 cells Lung squamous cell carcinoma Homo sapiens CVCL_1731
NCI-H196 cells Lung small cell carcinoma Homo sapiens CVCL_1509
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H2170 cells Lung squamous cell carcinoma Homo sapiens CVCL_1535
NCI-H647 cells Lung adenosquamous carcinoma Homo sapiens CVCL_1574
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
NCI-H838 cells Lung adenocarcinoma Homo sapiens CVCL_1594
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
NCI-H322 cells Lung adenocarcinoma Homo sapiens CVCL_1556
A-498 cells Renal cell carcinoma Homo sapiens CVCL_1056
In Vivo Model
Tumours were initiated in 4-8-week-old female NOD. CB17 Scid/J mice. Orthotopically in the mouse mammary gland, by implantation of 500,000 cells in 25 ul 33% Matrigel into the fourth mouse mammary fat pad; subcutaneously, by injection of 500,000 cells in 100 ul 33% Matrigel into the left or right flank of the mouse; via tail vein by injection of 500,000 cells in 150 ul RPMI into the mouse tail vein; and via intratracheal instillation by instilling 200,000 cells in 50 ul 2 mM EDTA as described. Cancer cells were transduced with viral shRNAs, selected for 3 days with puromycin, and allowed to recover for one day before introduction into mice. For experiments comparing subcutaneous and lung tumour formation, shRNA transduced cells were prepared at the same time and injected on the same day. Animals were imaged by IVIS (Perkin Elmer) 15 min following injection subcutaneously into the neck scruff with XenoLight d-Luciferin (165 mg per kg body weight, Perkin Elmer). Average luminescence was quantified per mouse from equal sized bins covering the mouse thorax. For experiments in which tumour growth was measured upon drug treatment, MDA-MB-231 cells, implanted as described above, were allowed to form palpable tumours (~4 mm diameter) and mice were sorted into treatment groups as described below. PEG-Cyst(e)inase was delivered via intraperitoneal injection at 50 mg per kg body weight every 3 days, SSA was delivered by daily intraperitoneal injection at 250 mg per kg body weight, and BSO was delivered in the drinking water at 20 mM with 5 mg ml-1 sucralose.

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Response regulation NFS1 suppression induced TFRC expression and repressed FTH1 and cytoplasmic aconitase activity. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [19]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator LINC00597 (IncRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
HEK-293T cells Normal Homo sapiens CVCL_0063
Response regulation This study indicated that cinobufotalin induced ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin might provide novel therapeutic targets for lung cancer therapy.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [19]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator hsa-miR-367-3p (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
SK-MES-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0630
HEK-293T cells Normal Homo sapiens CVCL_0063
Response regulation This study indicated that cinobufotalin induced ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin might provide novel therapeutic targets for lung cancer therapy.
Stearoyl-CoA desaturase (SCD)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [20]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Lymphoid-specific helicase (HELLS) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model MRC-5 cells Normal Homo sapiens CVCL_0440
HBE1 cells Normal Homo sapiens CVCL_0287
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
NCI-H522 cells Non-small cell lung carcinoma Homo sapiens CVCL_1567
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
95C cells Lung giant cell carcinoma Homo sapiens CVCL_7109
95D cells Lung giant cell carcinoma Homo sapiens CVCL_7110
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
SCID Mice (Hunan SJA Laboratory Animal Co.Ltd.) were injected with A549 (1 x 106 cells/mouse) or H358 (2 x 106 cells/mouse) cells via mammary fat pad (10 mice/group). Mice with A549 or H358 cells were imaged from dorsal and ventral views every three days.

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Response regulation LSH (HELLS) is involved in ferroptosis and is a potential therapeutic target in cancer because of its crucial role in ferroptosis. LSH functioned as an oncogene in lung cancer in vitro and in vivo. And LSH promotes the lipid metabolic genes, including SCD1 and FADS2.
Solute carrier family 40 member 1 (SLC40A1)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [21]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator Ubiquitin carboxyl-terminal hydrolase 35 (USP35) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
HBE1 cells Normal Homo sapiens CVCL_0287
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
In Vivo Model
BALB/c nude mice (4-5 weeks old) were obtained from HFK Bioscience Co., Ltd (Beijing, China) and maintained in a SPF barrier system. H460, H1299 or H1650 cell lines at a dose of 1 x 106 with or without USP35 manipulation were subcutaneously injected into the right dorsal flank of the nude mice.

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Response regulation USP35 was abundant in human lung cancer tissues and cell lines. USP35 knockdown promoted ferroptosis, and inhibited cell growth, colony formation, and tumor progression in lung cancer cells. Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [22]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-302a-3p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
BEAS-2B cells Normal Homo sapiens CVCL_0168
HBE1 cells Normal Homo sapiens CVCL_0287
Response regulation The miR-302a-3p mimic directly bound to the 3-UTR of FPN and decreased its protein expression, thereby causing intracellular iron overload and ferroptotic cell death, while the miR-302a-3p inhibitor significantly prevented erastin/RSL3-induced ferroptosis and tumor suppression. miR-302a-3p functions as a tumor inhibitor, via targeting ferroportin to induce ferroptosis of non-small cell lung cancer.
Sodium-coupled neutral amino acid symporter 1 (SLC38A1)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [23]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator OGFRP1 (IncRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
Male nude mice (5-week-old) were purchased from Jinan Pengyue Animal Breeding Center (Jinan, China). Next, mice models were established by subcutaneously injecting A549 cells (1 x 106 cells/100 uL) into the right armpit flanks, which were stably transfected with sh-NC or sh-OGFRP1. Tumor formation was monitored and tumor volume was calculated every week for 5 weeks according to the formula: tumor volume = 1/2 (length x width2). Totally 35 days upon injection, the mice were euthanized and the tumors were dissected out from the right armpit flanks and weighted. The tumor tissues of nude mice with lung cancer were snap-frozen in liquid nitrogen immediately and stored at -80 for further research.

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Response regulation OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [23]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator hsa-miR-299-3p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
BEAS-2B cells Normal Homo sapiens CVCL_0168
In Vivo Model
Male nude mice (5-week-old) were purchased from Jinan Pengyue Animal Breeding Center (Jinan, China). Next, mice models were established by subcutaneously injecting A549 cells (1 x 106 cells/100 uL) into the right armpit flanks, which were stably transfected with sh-NC or sh-OGFRP1. Tumor formation was monitored and tumor volume was calculated every week for 5 weeks according to the formula: tumor volume = 1/2 (length x width2). Totally 35 days upon injection, the mice were euthanized and the tumors were dissected out from the right armpit flanks and weighted. The tumor tissues of nude mice with lung cancer were snap-frozen in liquid nitrogen immediately and stored at -80 for further research.

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Response regulation OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.
Prostaglandin G/H synthase 2 (PTGS2)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [24]
Target for Ferroptosis Marker
Responsed Disease Lung squamous cell carcinoma [ICD-11: 2C25]
Responsed Regulator Basic helix-loop-helix ARNT-like protein 1 (BMAL1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HT1080 cells in 100 ul of phosphate-buffered saline (PBS) were injected subcutaneously at the right of the dorsal midline in 6- to 8-week-old female athymic nude mice (no. 490, Charles River Laboratories).

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Response regulation The autophagy-mediated degradation of ARNTL facilitates EGLN2 expression, thus destabilizing the prosurvival factor HIF1A, ultimately favoring lipid peroxidation and cell death. And the HIF1A inhibitor chetomin enhanced the anticancer activity of RSL3, PTGS2 mRNA expression in Lung squamous cell carcinoma.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [24]
Target for Ferroptosis Marker
Responsed Disease Lung squamous cell carcinoma [ICD-11: 2C25]
Responsed Regulator Prolyl hydroxylase EGLN2 (EGLN2) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 HT1080 cells in 100 ul of phosphate-buffered saline (PBS) were injected subcutaneously at the right of the dorsal midline in 6- to 8-week-old female athymic nude mice (no. 490, Charles River Laboratories).

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Response regulation The autophagy-mediated degradation of ARNTL facilitates EGLN2 expression, thus destabilizing the prosurvival factor HIF1A, ultimately favoring lipid peroxidation and cell death. And the HIF1A inhibitor chetomin enhanced the anticancer activity of RSL3, PTGS2 mRNA expression in Lung squamous cell carcinoma.
NADPH oxidase 4 (NOX4)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [32]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator Epidermal growth factor receptor (EGFR) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model hTERT-HME1 cells Normal Homo sapiens CVCL_3383
H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
In Vivo Model
2.5 x 105 NCI-H1650 cells were inoculated 1:1 in Matrigel: PBS (100 mL) by subcutaneous injection into eight non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma male mice. Tumors were allowed to engraft and grow for 30 days (tumor volume averaged ~200 mm3) and mice treated by intraperitoneal (i.p.) injection with 100 mg/kg cyst(e)inase or 100 mg/kg heat-inactivated cyst(e)inase (n = 4 ea.) on day 30, with a second dose given on day 33. Mice were necropsied 24 hr after the second dose.

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Response regulation In non-small-cell lung cancer (NSCLC) cells, active MAPK signaling downstream of active EGFR can sensitize cells to ferroptosis upon cystine depletion. Sensitization involves both impaired detoxification of lipid peroxides, due to reduced expression of GPX4, and generation of hydrogen peroxide, via NOX4.
Lysophospholipid acyltransferase 5 (LPCAT3)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [43]
Target for Ferroptosis Driver
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Cir93 (circRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
All athymic nude mice (6-week-old) were purchased from Jiesijie (Shanghai, China). To generate routine cell-derived xenograft (CDX) mouse models, established LUAD cells (initial 5 x 106) were subcutaneously injected into the bilateral dorsal flank of athymic nude mice. To generate H1975/A549 cell-implanted intrapulmonary LUAD mice, athymic nude mice were intrapulmonarily injected with cells (5 x 106) under anesthesia and then intranasally administered adeno-associated virus 5 (AAV5) particles (2 x 1012 viral particles/mL, Genomeditech, Shanghai, China) 3 weeks later. To generate patient-derived xenograft (PDX) mouse models, fresh LUAD tissues with a size of 2-3 mm3 were subcutaneously implanted into athymic nude mice. After successful passage, the PDX mice were used for further studies.

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Response regulation Intracellular cir93-FABP3 interactions are critical to upregulate FABP3 to reduce global AA via reactions with taurine. The product of AA and taurine (i.e., NAT) prevents AA incorporation into the plasma membrane, thus further reducing the opportunity for PUFA peroxidation in the membrane. NAT reduces ACSL4, LPCAT3 and PLTP. Exosome and cir93 are critical to desensitize lung adenocarcinoma to ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [43]
Target for Ferroptosis Driver
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Fatty acid-binding protein, heart (FABP3) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model H1650-ER1 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_4V01
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H358 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1559
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
All athymic nude mice (6-week-old) were purchased from Jiesijie (Shanghai, China). To generate routine cell-derived xenograft (CDX) mouse models, established LUAD cells (initial 5 x 106) were subcutaneously injected into the bilateral dorsal flank of athymic nude mice. To generate H1975/A549 cell-implanted intrapulmonary LUAD mice, athymic nude mice were intrapulmonarily injected with cells (5 x 106) under anesthesia and then intranasally administered adeno-associated virus 5 (AAV5) particles (2 x 1012 viral particles/mL, Genomeditech, Shanghai, China) 3 weeks later. To generate patient-derived xenograft (PDX) mouse models, fresh LUAD tissues with a size of 2-3 mm3 were subcutaneously implanted into athymic nude mice. After successful passage, the PDX mice were used for further studies.

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Response regulation Intracellular cir93-FABP3 interactions are critical to upregulate FABP3 to reduce global AA via reactions with taurine. The product of AA and taurine (i.e., NAT) prevents AA incorporation into the plasma membrane, thus further reducing the opportunity for PUFA peroxidation in the membrane. NAT reduces ACSL4, LPCAT3 and PLTP. Exosome and cir93 are critical to desensitize lung adenocarcinoma to ferroptosis.
Heme oxygenase 1 (HMOX1)
In total 4 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Betulin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRASmutant non-small-cell lung cancer (NSCLC) cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [26]
Target for Ferroptosis Driver
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Gefitinib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
Nude mice (5 weeks) were purchased from SLAC Int. (Shanghai, China). A549 cells (6 x 107 /ml) were collected and mixed with Matrigel (Corning, USA) at a 1:1 ratio by volume. Then, 100 ul cells were injected subcutaneously into the back region of nude mice to generate tumors with a size of 100 mm3 . Mice were randomly divided into four groups (n = 5/group): the control group, betulin group (10 mg/kg), gefitinib group (30 mg/kg), and the combined group. The control group was orally administered vehicle, while the betulin group, gefitinib group, and the combined group were orally administered betulin, gefitinib, and betulin plus gefitinib every other day. The tumor size and mice body weight were measured every other day too, and the volume was calculated according to the formula: tumor size (mm3 ) = (length x width2 ) x 0.5.

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Response regulation The expression of SCL7A11, GPX4, and FTH1, which are negative regulators of ferroptosis, was significantly decreased under the combinative treatment of betulin and gefitinib. Moreover, the positive regulatory protein HO-1 was increased. These findings reiterated that the combination of betulin with gefitinib could trigger ferroptosis in KRASmutant non-small-cell lung cancer (NSCLC) cells.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [30]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug Ginkgetin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
SPC-A1 cells Endocervical adenocarcinoma Homo sapiens CVCL_6955
In Vivo Model
Briefly, when tumours on transplanted nude mice reached around 100 mm3, the mice were randomized divided into eight groups: control, ginkgetin, DDP, ginkgetin + DDP, UAMC 3203, ginkgetin + UAMC 3203, DDP + UAMC 3203, ginkgetin + DDP + UAMC 3203. Both DDP (3 mg/kg) and ginkgetin (30 mg/kg) were administered by intraperitoneal injection, with 2 - 3 times per week and once per day, respectively. UAMC 3203 (10 mg/kg) was administered 5 days/week by intraperitoneally injection. Tumour size and body weight were measured 3 times per week. After dosing 31 days, the nude mice were sacrificed, and tumours were removed and weighed.

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Response regulation The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured non-small cell lung cancer (NSCLC) cells.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [38]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Drug S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
In Vivo Model
When tumor volumes in xenograft nude mice reached an average of roughly 100 mm3, the mice were randomly divided into 3 groups of 6 mice each: control, ShtIX, and ShtIX + Fer-1. The treated group received ShtIX or ShtIX combined with Fer-1 injections into the tail vein of the mice every three days for 7 times, whereas the control group received saline. Every four days, the volume and weight of the tumors were measured. As soon as the test was completed, the nude mice were slaughtered, and the tumor tissues were retrieved. The in vivo experiments were approved by the Animal Care and Use Committee of Hainan Medical College and following the animal rules.

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Response regulation S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane (ShtIX) caused ferroptosis in Non-small cell lung cancer (NSCLC) cells, and inhibiting the Nrf2/HO-1 pathway can considerably exacerbate the effect of ShtIX-induced ferroptosis.
Ferroptosis suppressor protein 1 (AIFM2)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [47]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator hsa-miR-4443 (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
16HBE14o- cells Normal Homo sapiens CVCL_0112
PG-CL3 cells Lung giant cell carcinoma Homo sapiens CVCL_4391
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
BALB/c nude mice (male, 4 weeks old) were purchased from the Animal Center of Nanjing University with free access to water and food. A549 cells (106 cells per mouse) transfected with miR-4443 mimic or mimic-NC were injected subcutaneously to generate subcutaneous tumors. Tumor volume was recorded.

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Response regulation METTL3 was confirmed as a direct target gene of miR-4443. Further mechanistic analysis showed that miR-4443 regulated the expression of FSP1 in an m6A manner via METLL3. A high level of exosomal miR-4443 conferred cisplatin resistance in non-small cell lung carcinoma (NSCLC) via METTL3/FSP1-mediated ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [47]
Target for Ferroptosis Suppressor
Responsed Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
Responsed Regulator N6-adenosine-methyltransferase catalytic subunit (METTL3) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
16HBE14o- cells Normal Homo sapiens CVCL_0112
PG-CL3 cells Lung giant cell carcinoma Homo sapiens CVCL_4391
NCI-H460 cells Lung large cell carcinoma Homo sapiens CVCL_0459
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
BALB/c nude mice (male, 4 weeks old) were purchased from the Animal Center of Nanjing University with free access to water and food. A549 cells (106 cells per mouse) transfected with miR-4443 mimic or mimic-NC were injected subcutaneously to generate subcutaneous tumors. Tumor volume was recorded.

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Response regulation METTL3 was confirmed as a direct target gene of miR-4443. Further mechanistic analysis showed that miR-4443 regulated the expression of FSP1 in an m6A manner via METLL3. A high level of exosomal miR-4443 conferred cisplatin resistance in non-small cell lung carcinoma (NSCLC) via METTL3/FSP1-mediated ferroptosis.
Fatty acid CoA ligase Acsl3 (ACSL3)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [48]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) Suppressor
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
SW1990 cells Pancreatic adenocarcinoma Homo sapiens CVCL_1723
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
In Vivo Model
Igf2bp3-/- mice were generated by Cyagen Biosciences (Guangzhou,China). Mettl3-/- mice were obtained as described in our previous study. H1299 cells with or without IGF2BP3 overexpression were digested and adjusted to a density of 5 x 106 cells/200 uL. Next, 200 uL of cells were injected into the right armpit of each 4-6-week-old athymic nude mouse (Jiesijie, Shanghai, China). The weight and tumor size of nude mice were measured. Each group contained five mice. After 2 weeks, mice were injected daily with dimethyl sulfoxide (DMSO, Beyotime Biotechnology, Shanghai, China) with or without imidazole ketone erastin (IKE, 50 mg/kg, MedChemExpress, Monmouth, NJ, USA) or rigosertib (RIG, 250 mg/kg, Selleck, Houston, TX, USA).

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Response regulation After IGF2BP3 overexpression, expression levels and mRNA stabilities of these anti-ferroptotic factors were successfully sustained. Notably, significant correlations between SLC3A2, ACSL3, and IGF2BP3 were revealed in clinical Lung adenocarcinoma specimens, further establishing the essential role of IGF2BP3 in desensitizing ferroptosis. Inducing ferroptosis has been gradually accepted as an alternative strategy to treat tumors.
Diamine acetyltransferase 1 (SAT1)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [49]
Target for Ferroptosis Driver
Responsed Disease Lung cancer [ICD-11: 2C25]
Responsed Regulator E3 ubiquitin-protein ligase RNF113A (RNF113A) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
HEK293 cells Normal Homo sapiens CVCL_0045
PCS-201-012 (Human normal dermal fibroblasts)
In Vivo Model
Five millions of control or RNF113A-depleted Cisplatin-resistant A549 cells were transplanted into immunodeficient NOD/SCID 8 weeks old mice. Tumors were grown up to 0.1-0.2 mm3 and mice were then treated with Cisplatin (1 mg/kg) six times every 3 days. Seven mice were used per experimental conditions. No randomization of mice was used.

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Response regulation RNF113A, whose loss-of-function causes the X-linked trichothiodystrophy, is overexpressed in lung cancer and protects from Cisplatin-dependent cell death. RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis due to enhanced SAT1 expression, and increased production of ROS due to altered Noxa1 expression.
CDGSH iron-sulfur domain-containing protein 1 (CISD1)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [56]
Target for Ferroptosis Driver/Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator hsa-miR-101-3p (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell infiltration
In Vitro Model BEAS-2B cells Normal Homo sapiens CVCL_0168
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
Response regulation The study found GSEC, CISD1, ATP5MC3, and PGD to be upregulated, with miRNA-101-3p downregulated, in the setting of lung adenocarcinoma (LUAD). Immunohistochemical analysis revealed CISD1, ATP5MC3, and PGD overexpression in LUAD tissue samples; CISD1 knockdown was noted to significantly inhibit LUAD proliferation and migration.
4F2 cell-surface antigen heavy chain (SLC3A2)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [31]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25]
Responsed Regulator Protein LYRIC (MTDH) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
DMS53 cells Lung small cell carcinoma Homo sapiens CVCL_1177
DMS 273 cells Lung small cell carcinoma Homo sapiens CVCL_1176
KLE cells Endometrial adenocarcinoma Homo sapiens CVCL_1329
AN3CA cells Endometrial adenocarcinoma Homo sapiens CVCL_0028
RL95-2 cells Endometrial adenosquamous carcinoma Homo sapiens CVCL_0505
HEC-1-A cells Endometrial adenocarcinoma Homo sapiens CVCL_0293
Ishikawa cells Endometrial adenocarcinoma Homo sapiens CVCL_2529
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Hec50 cells Endometrial adenocarcinoma Homo sapiens CVCL_2929
In Vivo Model
To generate tumor xenograft models, 5 x 106 MTDH WT and KO MDA-MB-231 cells were injected into the second and fifth mammary fat pads (both sides, total four sites) of the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG, Jackson Laboratories, Bar Harbor, ME) immunodeficient female mice. To study the metastasis from this orthotopic mouse model, tumor volumes were allowed to grow to ~1000 mm3, after which livers were resected to examine incidence as well as tumor burden of liver metastasis.

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Response regulation Metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system Xc-heterodimerization partner), at both the messenger RNA and protein levels in Lung adenocarcinoma.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [51]
Target for Ferroptosis Suppressor
Responsed Disease Lung adenocarcinoma [ICD-11: 2C25.0]
Responsed Regulator 3'-5' RNA helicase YTHDC2 Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HEK-293T cells Normal Homo sapiens CVCL_0063
BEAS-2B cells Normal Homo sapiens CVCL_0168
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
PC-9 cells Lung adenocarcinoma Homo sapiens CVCL_B260
NCI-H1975 cells Lung adenocarcinoma Homo sapiens CVCL_1511
NCI-H441 cells Lung papillary adenocarcinoma Homo sapiens CVCL_1561
NCI-H1650 cells Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
HCC827 cells Lung adenocarcinoma Homo sapiens CVCL_2063
NCI-H292 cells Lung mucoepidermoid carcinoma Homo sapiens CVCL_0455
Calu-1 cells Lung squamous cell carcinoma Homo sapiens CVCL_0608
In Vivo Model
For xenograft experiments, 1.5 x 107 Doxocycline (Dox)-inducible YTHDC2-expressing H1299 cells were subcutaneously injected into 4-6-week-oldathymic nude mice. At day 14 post inoculation, mice were randomly divided into 2 groups for further administrating with or without Dox (30 mg/kg) every other day. Tumors were assessed after sacrificing the mice at day 28 after implantation.

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Response regulation The m6A reader YT521-B homology containing 2 (YTHDC2) has been identified to inhibit lung adenocarcinoma (LUAD) tumorigenesis by suppressing solute carrier 7A11 (SLC7A11)-dependent antioxidant function. YTHDC2 also suppresses SLC3A2 subunit via inhibiting HOXA13-mediated SLC3A2 transcription.
References
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Ref 58 Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells. 2020 Oct 9;9(10):2259. doi: 10.3390/cells9102259.
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Ref 60 GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail. Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2219585120. doi: 10.1073/pnas.2219585120. Epub 2023 Apr 5.
Ref 61 Overexpression of LINC00551 promotes autophagy-dependent ferroptosis of lung adenocarcinoma via upregulating DDIT4 by sponging miR-4328. PeerJ. 2022 Oct 12;10:e14180. doi: 10.7717/peerj.14180. eCollection 2022.
Ref 62 The mitochondrial Ca(2+) uptake regulator, MICU1, is involved in cold stress-induced ferroptosis. EMBO Rep. 2021 May 5;22(5):e51532. doi: 10.15252/embr.202051532. Epub 2021 Apr 6.
Ref 63 A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53. Cancer Res. 2018 Jul 1;78(13):3484-3496. doi: 10.1158/0008-5472.CAN-17-3454. Epub 2018 Mar 27.
Ref 64 Identification of critical ferroptosis regulators in lung adenocarcinoma that RRM2 facilitates tumor immune infiltration by inhibiting ferroptotic death. Clin Immunol. 2021 Nov;232:108872. doi: 10.1016/j.clim.2021.108872. Epub 2021 Oct 11.
Ref 65 Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer. Cell Rep. 2020 Dec 1;33(9):108444. doi: 10.1016/j.celrep.2020.108444.
Ref 66 KIF20A is associated with clinical prognosis and synergistic effect of gemcitabine combined with ferroptosis inducer in lung adenocarcinoma. Front Pharmacol. 2022 Sep 26;13:1007429. doi: 10.3389/fphar.2022.1007429. eCollection 2022.
Ref 67 Aberrant expression of KDM1A inhibits ferroptosis of lung cancer cells through up-regulating c-Myc. Sci Rep. 2022 Nov 10;12(1):19168. doi: 10.1038/s41598-022-23699-4.
Ref 68 Construction of a ferroptosis scoring system and identification of LINC01572 as a novel ferroptosis suppressor in lung adenocarcinoma. Front Pharmacol. 2023 Jan 4;13:1098136. doi: 10.3389/fphar.2022.1098136. eCollection 2022.
Ref 69 Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ. 2019 Nov;26(11):2329-2343. doi: 10.1038/s41418-019-0304-y. Epub 2019 Feb 20.
Ref 70 Nanomedicine promotes ferroptosis to inhibit tumour proliferation in vivo. Redox Biol. 2021 Jun;42:101908. doi: 10.1016/j.redox.2021.101908. Epub 2021 Feb 20.
Ref 71 Ferroptosis-related gene AKR1C1 predicts the prognosis of non-small cell lung cancer. Cancer Cell Int. 2021 Oct 26;21(1):567. doi: 10.1186/s12935-021-02267-2.
Ref 72 LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis. Signal Transduct Target Ther. 2020 Sep 3;5(1):187. doi: 10.1038/s41392-020-00297-2.