Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10150)
Regulator Name Signal transducer and activator of transcription 3 (STAT3)
Synonyms
Acute-phase response factor
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Gene Name STAT3
Gene ID 6774
Regulator Type Protein coding
Uniprot ID P40763
Sequence
MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNL
LGEIDQQYSRFLQESNVLYQHNLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAA
TAAQQGGQANHPTAAVVTEKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLK
SQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTDEEL
ADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQ
HRPMLEERIVELFRNLMKSAFVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNY
QLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESNNGSLSAEFKHLTLREQRCGN
GGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY
NMLTNNPKNVNFFTKPPIGTWDQVAEVLSWQFSSTTKRGLSIEQLTTLAEKLLGPGVNYS
GCQITWAKFCKENMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILST
KPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQLNNMSFAEIIMGYKIM
DATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGSAAPYLKTKFICVTPTTCSN
TIDLPMSPRTLDSLMQFGNNGEGAEPSAGGQFESLTFDMELTSECATSPM

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Family Transcription factor STAT family
Function
Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL31RA. Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity. Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1. Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation. May play an apoptotic role by transctivating BIRC5 expression under LEP activation. Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity. Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion.

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HGNC ID
HGNC:11364
KEGG ID hsa:6774
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
STAT3 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
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Browse Disease
Browse Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Drug Peoniflorin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

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Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Drug Peoniflorin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Osteosarcoma ICD-11: 2B51
 Disease Info 
Responsed Drug Bavachin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MG-63 cells Osteosarcoma Homo sapiens CVCL_0426
HOS cells Osteosarcoma Homo sapiens CVCL_0312
Response regulation Bavachin could induce Osteosarcoma cell ferroptosis. Furthermore, bavachin elevated intracellular ferrous iron levels by increasing TFRC and DMT1 expression and decreasing FTH and FTL expressions. Bavachin also reduced SLC7A11 and GPX4 expression and promoted ROS and MDA accumulation by downregulating p-STAT3 to upregulate P53 expression.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [5]
Target for Ferroptosis Suppressor
Responsed Disease Head neck squamous cell carcinoma ICD-11: 2D60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ferroptosis hsa04216
JAK-STAT signaling pathway hsa04630
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HN4 cells Clear cell renal cell carcinoma Homo sapiens CVCL_IS30
CAL-27 cells Tongue adenosquamous carcinom Homo sapiens CVCL_1107
In Vivo Model
Four-week-old male BALB/c-nu mice were purchased from the Shanghai Laboratory Animal Center (Shanghai, China). About 4 x 106 CAL27 cells were stably transfected with lentivirus. After administration of 2 ug/mL puromycin for three days, transfection efficiency was confirmed by western blotting. Approximately 2 x 106 transfected cells were subcutaneously injected into flanks. For the drug-administration study, 20 mg/kg erastin (S7242, Selleck Chemicals) were administrated intraperitoneally twice every other day. Approximately 20 uL IL-6 (10 ug/mL, PeproTech, USA) were given intratumorally twice every other day.

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Response regulation The study demonstrate the critical role of IL-6-induced ferroptosis resistance during head and neck squamous cell carcinoma carcinogenesis. The IL-6/ STAT3/xCT (encoded by SLC7A11) axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.
Unspecific Target [Unspecific Target]
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [3]
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Responsed Drug Dimethyl fumarate Approved
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-431 cells Skin squamous cell carcinoma Homo sapiens CVCL_0037
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HaCaT cells Normal Homo sapiens CVCL_0038
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
SK-MEL-28 cells Cutaneous melanoma Homo sapiens CVCL_0526
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
For the VFN-D1 patient-derived and the HBL-1 xenograft mouse models, adult female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were implanted subcutaneously with 1 x 107 cells in PBS (300 ul). Once mice developed palpable tumors, the animals were randomized into control, DMF (daily i.p. treatment with 500 ul of 3 mg/ml DMF in PBS), ABT-199 (daily p.o. treatment with 100 mg/kg in ethanol/PhosalG/PEG400) or DMF+ABT-199 treated groups.

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Response regulation Dimethyl fumarate (DMF) induces lipid peroxidation and thus ferroptosis, particularly in GCB diffuse large B-cell lymphoma (DLBCL). In ABC DLBCL cells, which are addicted to NF-kB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases .
Experiment 2 Reporting the Ferroptosis Target of This Regulator [4]
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Responsed Drug Artesunate Investigative
 Drug Info 
Pathway Response JAK-STAT signaling pathway hsa04630
Ferroptosis hsa04216
Autophagy hsa04140
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
In Vitro Model
 U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-4 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_0539
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female NOD/SCID mice (age, 6 weeks; body weight, 20 ± 2 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd., maintained under pathogen-free conditions and allowed free access to sterilized food and water. After a week of adaptation to their surroundings, 1 x 107 U2932 cells were subcutaneously injected into the right flank near the hind leg of each mouse. Following the growth of palpable tumors (tumor volume of 50-100 mm3), the mice were randomly divided into two groups (n = 5 mice/group) and treated with 100 ul normal saline (NS) or ART (120 mg/kg/day) via intraperitoneal injection.

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Response regulation Artesunate (ART) was found to exert its effects via inhibition of STAT3 activation. ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in diffuse large B cell lymphoma (DLBCL) cells.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [6]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
In Vivo Model
The effect of levobupivacaine on tumor growth of breast cancer in vivo was assessed in the Balb/c nude mice (male, 4-week-old) (n = 5). About 1 x 107 cells MDA-MB-231 cells transfected with control shRNA or circRHOT1 shRNA were subcutaneously injected into the mice. After 5 days of injection, we measured tumor growth every 5 days. We sacrificed the mice after 30 days of injection, and tumors were scaled.

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Response regulation The depletion of circRHOT1 was able to repress the proliferation and induce the apoptosis of breast cancer cells. CircRHOT1 knockdown could remarkably inhibit the invasion and migration in the breast cancer cells. Mechanically, circRHOT1 contributed to malignant progression and attenuated ferroptosis in breast cancer by the miR-106a-5p/ STAT3 axis.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4) [Driver]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [7]
Target for Ferroptosis Driver
Responsed Disease Health ICD-11: N.A.
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 MCF-10A cells Normal Homo sapiens CVCL_0598
SUM159PT cells Breast pleomorphic carcinoma Homo sapiens CVCL_5590
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
In Vivo Model
PDX models of triple-negative breast cancer were obtained from the Dana-Farber Cancer Institute and propagated in NSG mice. Tumors were harvested and digested using collagenase at 37. Once digested, the cells were filtered using a cell strainer (40 um), washed twice with PBS, and plated in DMEM/F12 (containing 10% FBS).

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Response regulation 64-mediated activation of Src and STAT3 suppresses expression of ACSL4, an enzyme that enriches membranes with long polyunsaturated fatty acids and is required for ferroptosis.
Glioblastoma [ICD-11: 2A00]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Responsed Drug Peoniflorin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Responsed Drug Peoniflorin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Osteosarcoma [ICD-11: 2B51]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Responsed Drug Bavachin Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MG-63 cells Osteosarcoma Homo sapiens CVCL_0426
HOS cells Osteosarcoma Homo sapiens CVCL_0312
Response regulation Bavachin could induce Osteosarcoma cell ferroptosis. Furthermore, bavachin elevated intracellular ferrous iron levels by increasing TFRC and DMT1 expression and decreasing FTH and FTL expressions. Bavachin also reduced SLC7A11 and GPX4 expression and promoted ROS and MDA accumulation by downregulating p-STAT3 to upregulate P53 expression.
Diffuse large B-cell lymphoma [ICD-11: 2A81]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Responsed Drug Dimethyl fumarate Approved
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-431 cells Skin squamous cell carcinoma Homo sapiens CVCL_0037
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HaCaT cells Normal Homo sapiens CVCL_0038
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
SK-MEL-28 cells Cutaneous melanoma Homo sapiens CVCL_0526
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
For the VFN-D1 patient-derived and the HBL-1 xenograft mouse models, adult female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were implanted subcutaneously with 1 x 107 cells in PBS (300 ul). Once mice developed palpable tumors, the animals were randomized into control, DMF (daily i.p. treatment with 500 ul of 3 mg/ml DMF in PBS), ABT-199 (daily p.o. treatment with 100 mg/kg in ethanol/PhosalG/PEG400) or DMF+ABT-199 treated groups.

    Click to Show/Hide
Response regulation Dimethyl fumarate (DMF) induces lipid peroxidation and thus ferroptosis, particularly in GCB diffuse large B-cell lymphoma (DLBCL). In ABC DLBCL cells, which are addicted to NF-kB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases .
Experiment 2 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Responsed Drug Artesunate Investigative
 Drug Info 
Pathway Response JAK-STAT signaling pathway hsa04630
Ferroptosis hsa04216
Autophagy hsa04140
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
In Vitro Model
 U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-4 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_0539
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female NOD/SCID mice (age, 6 weeks; body weight, 20 ± 2 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd., maintained under pathogen-free conditions and allowed free access to sterilized food and water. After a week of adaptation to their surroundings, 1 x 107 U2932 cells were subcutaneously injected into the right flank near the hind leg of each mouse. Following the growth of palpable tumors (tumor volume of 50-100 mm3), the mice were randomly divided into two groups (n = 5 mice/group) and treated with 100 ul normal saline (NS) or ART (120 mg/kg/day) via intraperitoneal injection.

    Click to Show/Hide
Response regulation Artesunate (ART) was found to exert its effects via inhibition of STAT3 activation. ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in diffuse large B cell lymphoma (DLBCL) cells.
Head neck squamous cell carcinoma [ICD-11: 2D60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [5]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ferroptosis hsa04216
JAK-STAT signaling pathway hsa04630
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HN4 cells Clear cell renal cell carcinoma Homo sapiens CVCL_IS30
CAL-27 cells Tongue adenosquamous carcinom Homo sapiens CVCL_1107
In Vivo Model
Four-week-old male BALB/c-nu mice were purchased from the Shanghai Laboratory Animal Center (Shanghai, China). About 4 x 106 CAL27 cells were stably transfected with lentivirus. After administration of 2 ug/mL puromycin for three days, transfection efficiency was confirmed by western blotting. Approximately 2 x 106 transfected cells were subcutaneously injected into flanks. For the drug-administration study, 20 mg/kg erastin (S7242, Selleck Chemicals) were administrated intraperitoneally twice every other day. Approximately 20 uL IL-6 (10 ug/mL, PeproTech, USA) were given intratumorally twice every other day.

    Click to Show/Hide
Response regulation The study demonstrate the critical role of IL-6-induced ferroptosis resistance during head and neck squamous cell carcinoma carcinogenesis. The IL-6/ STAT3/xCT (encoded by SLC7A11) axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [6]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
In Vivo Model
The effect of levobupivacaine on tumor growth of breast cancer in vivo was assessed in the Balb/c nude mice (male, 4-week-old) (n = 5). About 1 x 107 cells MDA-MB-231 cells transfected with control shRNA or circRHOT1 shRNA were subcutaneously injected into the mice. After 5 days of injection, we measured tumor growth every 5 days. We sacrificed the mice after 30 days of injection, and tumors were scaled.

    Click to Show/Hide
Response regulation The depletion of circRHOT1 was able to repress the proliferation and induce the apoptosis of breast cancer cells. CircRHOT1 knockdown could remarkably inhibit the invasion and migration in the breast cancer cells. Mechanically, circRHOT1 contributed to malignant progression and attenuated ferroptosis in breast cancer by the miR-106a-5p/ STAT3 axis.
Health [ICD-11: N.A.]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [7]
Target Regulator Signal transducer and activator of transcription 3 (STAT3) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 MCF-10A cells Normal Homo sapiens CVCL_0598
SUM159PT cells Breast pleomorphic carcinoma Homo sapiens CVCL_5590
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
In Vivo Model
PDX models of triple-negative breast cancer were obtained from the Dana-Farber Cancer Institute and propagated in NSG mice. Tumors were harvested and digested using collagenase at 37. Once digested, the cells were filtered using a cell strainer (40 um), washed twice with PBS, and plated in DMEM/F12 (containing 10% FBS).

    Click to Show/Hide
Response regulation 64-mediated activation of Src and STAT3 suppresses expression of ACSL4, an enzyme that enriches membranes with long polyunsaturated fatty acids and is required for ferroptosis.
Peoniflorin [Investigative]
 Drug Info 
In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
 Target Info 
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Nuclear factor erythroid 2-related factor 2 (NFE2L2) Suppressor; Marker
 Target Info 
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Bavachin [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Inducer
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
 Target Info 
Responsed Disease Osteosarcoma ICD-11: 2B51
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MG-63 cells Osteosarcoma Homo sapiens CVCL_0426
HOS cells Osteosarcoma Homo sapiens CVCL_0312
Response regulation Bavachin could induce Osteosarcoma cell ferroptosis. Furthermore, bavachin elevated intracellular ferrous iron levels by increasing TFRC and DMT1 expression and decreasing FTH and FTL expressions. Bavachin also reduced SLC7A11 and GPX4 expression and promoted ROS and MDA accumulation by downregulating p-STAT3 to upregulate P53 expression.
Dimethyl fumarate [Approved]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [3]
Drug for Ferroptosis Inducer
Response Target Unspecific Target
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-431 cells Skin squamous cell carcinoma Homo sapiens CVCL_0037
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HaCaT cells Normal Homo sapiens CVCL_0038
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
SK-MEL-28 cells Cutaneous melanoma Homo sapiens CVCL_0526
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
For the VFN-D1 patient-derived and the HBL-1 xenograft mouse models, adult female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were implanted subcutaneously with 1 x 107 cells in PBS (300 ul). Once mice developed palpable tumors, the animals were randomized into control, DMF (daily i.p. treatment with 500 ul of 3 mg/ml DMF in PBS), ABT-199 (daily p.o. treatment with 100 mg/kg in ethanol/PhosalG/PEG400) or DMF+ABT-199 treated groups.

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Response regulation Dimethyl fumarate (DMF) induces lipid peroxidation and thus ferroptosis, particularly in GCB diffuse large B-cell lymphoma (DLBCL). In ABC DLBCL cells, which are addicted to NF-kB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases .
Artesunate [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [4]
Drug for Ferroptosis Inducer
Response Target Unspecific Target
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Pathway Response JAK-STAT signaling pathway hsa04630
Ferroptosis hsa04216
Autophagy hsa04140
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
In Vitro Model
 U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-4 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_0539
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female NOD/SCID mice (age, 6 weeks; body weight, 20 ± 2 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd., maintained under pathogen-free conditions and allowed free access to sterilized food and water. After a week of adaptation to their surroundings, 1 x 107 U2932 cells were subcutaneously injected into the right flank near the hind leg of each mouse. Following the growth of palpable tumors (tumor volume of 50-100 mm3), the mice were randomly divided into two groups (n = 5 mice/group) and treated with 100 ul normal saline (NS) or ART (120 mg/kg/day) via intraperitoneal injection.

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Response regulation Artesunate (ART) was found to exert its effects via inhibition of STAT3 activation. ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in diffuse large B cell lymphoma (DLBCL) cells.
References
Ref 1 Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells. J Oncol. 2022 Dec 28;2022:6093216. doi: 10.1155/2022/6093216. eCollection 2022.
Ref 2 Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells. Oxid Med Cell Longev. 2021 Oct 18;2021:1783485. doi: 10.1155/2021/1783485. eCollection 2021.
Ref 3 Dimethyl fumarate induces ferroptosis and impairs NF-B/STAT3 signaling in DLBCL. Blood. 2021 Sep 9;138(10):871-884. doi: 10.1182/blood.2020009404.
Ref 4 Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling. Cell Signal. 2021 Dec;88:110167. doi: 10.1016/j.cellsig.2021.110167. Epub 2021 Oct 7.
Ref 5 Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma. Cancer Lett. 2022 Feb 28;527:28-40. doi: 10.1016/j.canlet.2021.12.011. Epub 2021 Dec 10.
Ref 6 Circular RNA RHOT1 promotes progression and inhibits ferroptosis via mir-106a-5p/STAT3 axis in breast cancer. Aging (Albany NY). 2021 Mar 3;13(6):8115-8126. doi: 10.18632/aging.202608. Epub 2021 Mar 3.
Ref 7 The 64 integrin promotes resistance to ferroptosis. J Cell Biol. 2017 Dec 4;216(12):4287-4297. doi: 10.1083/jcb.201701136. Epub 2017 Sep 28.