Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10214)

Regulator Name	Kelch-like ECH-associated protein 1 (KEAP1)
Synonyms	Cytosolic inhibitor of Nrf2 Click to Show/Hide
Gene Name	KEAP1
Gene ID	9817
Regulator Type	Protein coding
Uniprot ID	Q14145
Sequence	MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHT KQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGM EVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLD PSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVR CESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDY LVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQV PRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGV IDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDG TNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVE TETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSG RSGVGVAVTMEPCRKQIDQQNCTC Click to Show/Hide
Family	KEAP1 family
Function	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome. Click to Show/Hide
HGNC ID	HGNC:23177
KEGG ID	hsa:9817

Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)

KEAP1 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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Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]

Target Info

In total 21 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	Apatinib		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/ Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[1]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Responsed Drug	Apatinib		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[2]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Responsed Drug	Tiliroside		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 10⁶ HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm³, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde. Click to Show/Hide
Response regulation	Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[3]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Responsed Drug	Withaferin A		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
	Cell adhesion molecules			hsa04514
Cell Process	Cell ferroptosis
	Cell proliferation
	Cell invasion
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	SNU-449 cells	Adult hepatocellular carcinoma	Homo sapiens	CVCL_0454
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
Response regulation	Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for Hepatocellular carcinoma therapy, especially for advanced hepatocellular carcinoma.
Experiment 5 Reporting the Ferroptosis Target of This Regulator				[4]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Melanoma		ICD-11: 2C30	Disease Info
Responsed Drug	Nobiletin		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	SK-MEL-28 cells	Cutaneous melanoma	Homo sapiens	CVCL_0526
Response regulation	Nobiletin could induce ferroptosis by regulating the GSK3B-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.
Experiment 6 Reporting the Ferroptosis Target of This Regulator				[5]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Vascular dementia		ICD-11: 6D81	Disease Info
Responsed Drug	Gastrodin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Male Sprague-Dawley rats (weight 260 ± 20 g; Guizhou Medical University Experimental Animal Center; Certificate No. SCXK2018-0001; Grant No. 2200483) were reared in a specific pathogen-free environment with 12 h light/dark cycle and 55% ± 10% humidity at a temperature of 20~25 , were provided with sufficient feed and sterile drinking water and fasted for 6 h before and after surgery. All animal experiments were performed in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. Click to Show/Hide
Response regulation	Gastrodin (GAS) inhibited ferroptosis in hippocampal neurons by activating the Nrf2/ Keap1-GPx4 signaling pathway, suggesting its possible application as a functional food for improving vascular dementia by inhibiting ferroptosis.
Experiment 7 Reporting the Ferroptosis Target of This Regulator				[6]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Parkinson disease		ICD-11: 8A00	Disease Info
Responsed Drug	L. lactis MG1363-pMG36e-GLP-1		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Colon tissues (Mouse colon tissues)
	hBCs (Brain cells)
In Vivo Model	Fifty male C57BL/6 mice provided by Hunan SJA Laboratory Animal Co., Ltd. (Changsha, China) resided in an animal house (temperature 26 ± 1 , humidity 50 ± 10%), in which the light was on for 12 h and off for 12 h. Mice were acclimatised for 1 week and allowed water and animal food with no limitations. Then, all mice were stochastically divided into 5 groups using random number tables available online (https://www.random-online.com/, accessed on 26 December 2021), including: (1) C group, a control group treated with normal saline for 7 consecutive days (n = 10); (2) M group, a model group with intraperitoneal injection of 20 mg/kg/day MPTP (Sigma-Aldrich, Taufkirchen, Germany, M0896) for 7 consecutive days (n = 10); (3) L group, treated with MPTP and 0.4 mg/kg/day liraglutide for 7 consecutive days (n = 10); (4) R group, treated with MPTP and 109 colony-forming unit (CFU) L. lactis MG1363 for 7 consecutive days via gavage (n = 10); (5) RG group, treated with MPTP and 109 CFUL. lactis MG1363-pMG36e-GLP-1 for 7 consecutive days via gavage (n = 10). All animals survived treatment and all animal experiments were administered from 9:00 to 12:00 in the morning to reduce systematic errors. Click to Show/Hide
Response regulation	L. lactis MG1363-pMG36e-GLP-1 exerts neurotrophic effects via activating the Keap1/Nrf2/GPX4 signalling pathway to down-regulate ACSL4 and up-regulate FSP1 to suppress ferroptosis. These results indicated that the neurotrophic effects of the next-generation probiotics L. lactis MG1363-pMG36e-GLP-1 against MPTP-induced Parkinsonism are mediated by modulating oxidative stress, inhibiting ferroptosis, and redressing dysbiosis.
Experiment 8 Reporting the Ferroptosis Target of This Regulator				[7]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Subarachnoid Hemorrhage		ICD-11: 8B01	Disease Info
Responsed Drug	Astragaloside IV		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hBCs (Brain cells)
In Vivo Model	SAH model was constructed by applying endovascular perforation in the rats, according to the protocol introduced in a previous study (Wei et al., 2020), except for slight modifications. Briefly, after performing intraperitoneal anesthesia with 40 mg/kg sodium pentobarbital, the right common carotid, external and internal carotid arteries of the rats were exposed and isolated. The right external carotid artery was ligated, and a 4-0 single-strand nylon thread was used to insert the right internal carotid artery through the stump of the external carotid artery and the bifurcation of the common carotid artery. When resistance is felt when the suture enters the intracranial segment, proceed approximately 3 mm to penetrate internal carotid artery at the bifurcation of middle cerebral artery. The suture was held in this position for 10 s and was then withdrawn. The rats in the Sham group went through an identical procedure, without the suture at the point of resistance. Throughout the experiment, the body temperature of the rats was sustained at around 37 by using a thermal blanket. After the wounds were sutured, the rats were placed in a separate cage and neurological function was closely observed. Click to Show/Hide
Response regulation	Astragaloside IV (AS-IV) triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of subarachnoid hemorrhage (SAH). The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. Ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway. The liberation of Nrf2 from Keap1, its cytoplasmic repressor will provoke Nrf2 accumulation in the nucleus.
Experiment 9 Reporting the Ferroptosis Target of This Regulator				[8]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Cerebral ischemia		ICD-11: 8B10	Disease Info
Responsed Drug	Astragaloside IV		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	SH-SY5Y cells	Neuroblastoma	Homo sapiens	CVCL_0019
In Vivo Model	Rats were randomly divided into the Sham, middle cerebral artery occlusion-reperfusion (MCAO/R), and MCAO/R + AST IV (28 mg/kg) groups. The MCAO/R + AST IV group was intragastrically injected with 10 mL/kg AST IV at 50, 26, and 2 h before modelling (Xiao et al., 2021). The Sham and MCAO/R groups received equal amounts of normal saline. As described previously, the modified Longa method (Longa et al., 1989) was used to establish the MCAO/R model. After anaesthesia with 2%sodium pentobarbital, the left common carotid artery(CCA), the external carotid artery(ECA), and the internal carotid artery(ICA) were isolated. The distal end of the ECA was ligated, a small incision was made at the stump of the ECA, and a suture (Batch number: 2636A2, Beijing Seinong Technology Co., Ltd., Beijing, China; head-end diameter: 0.36 ± 0.02 mm) was inserted into the ICA from the ECA through the bifurcation of the CCA. To achieve cerebral ischaemia, the head-end was used to block blood flow in the middle cerebral artery until the intracranial segment of the ICA was inserted. The suture was removed after 2 h, and follow-up experiments were performed 24 h after reperfusion. In the Sham group, the CCA, ECA, and ICA were exposed and separated, but no sutures were inserted. Penicillin powder was used to fight infection after operation. Click to Show/Hide
Response regulation	Astragaloside IV (AST IV) increased the P62 (SQSTM1) and Nrf2 levels and decreased the Keap1 levels. P62 silencing reduced the effects of AST IV on the P62/ Keap1/Nrf2 pathway and ferroptosis. Our findings suggest that AST IV mitigates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via activation of the P62/ Keap1/Nrf2 pathway.
Experiment 10 Reporting the Ferroptosis Target of This Regulator				[9]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Nonalcoholic fatty liver disease		ICD-11: DB92	Disease Info
Responsed Drug	Dehydroabietic acid		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HEK-293T cells	Normal	Homo sapiens	CVCL_0063
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	The male C57BL/6J mice (6-8 weeks, Beijing Vital River Laboratory Animal Technology Co., Ltd., China) were exposed to 12 h of light and darkness at temperature (22 ± 2 ), humidity (55%) with free access to water and food. All the mice were acclimated for 1 week before the experiment, then the mice were fed normal chow diet (NCD) and high-fat diet (HFD, D12492) for 12 weeks. The HFD group was divided into 3 groups (HFD, low dose of DA (DA-L, 10 mg/kg/d), high dose of DA (DA-H, 20 mg/kg/d),n = 8)). DA was administered by gavage for 9 weeks, and 0.5% CMC-Na was administered by NCD and HFD. Click to Show/Hide
Response regulation	Dehydroabietic acid (DA) inhibited ferroptosis and increased the expression of key genes such as ferroptosis suppressor protein 1 (FSP1) in vitro and vivo. In all, DA may bind with Keap1, activate Nrf2-ARE, induce its target gene expression, inhibit ROS accumulation and lipid peroxidation, and reduce HFD-induced nonalcoholic fatty liver disease (NAFLD).
Experiment 11 Reporting the Ferroptosis Target of This Regulator				[10]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Degenerative arthritis		ICD-11: FA05	Disease Info
Responsed Drug	Baicalein		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation
Experiment 12 Reporting the Ferroptosis Target of This Regulator				[11]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Endometrial hyperplasia		ICD-11: GA16	Disease Info
Responsed Drug	Guizhi Fuling Capsule		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	mUTs (Mouse uterine tissues)
In Vivo Model	Female C57BL/6 mice (8-week-old) were purchased from Model Animal Research Center of Nanjing University (Nanjing, China). Fifteen mice were randomly divided into three groups: Olive oil group, Estradiol group and Estradiol + IKE group. The Estradiol group was subcutaneously injected estradiol (50 ug/kg/day), Estradiol + IKE group was subcutaneously injected estradiol and intraperitoneally injected IKE (50 mg/kg) for 21 days, while the Olive oil group received the same volume of olive oil. In the experiment of exploring the improvement of GFC to EH, twenty mice were randomly divided into four groups: Olive oil group, Estradiol group, 75 mg/kg GFC group and 150 mg/kg GFC group. Except for Olive oil group, mice were subcutaneously daily injected with estradiol (50 ug/kg/day) for 21 days, while the Olive oil group received the same volume of olive oil. 75 mg/kg GFC group and 150 mg/kg GFC group were treated with GFC intragastrical administration. Click to Show/Hide
Response regulation	Guizhi Fuling Capsule (GFC) may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62 (SQSTM1)- Keap1-NRF2 pathway. GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.
Experiment 13 Reporting the Ferroptosis Target of This Regulator				[12]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Acute kidney failure		ICD-11: GB60	Disease Info
Responsed Drug	Entacapone		Approved	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HK-2 cells	Normal	Homo sapiens	CVCL_0302
In Vivo Model	Male C57BL/6 mice (8-10 weeks; 20-25 g) were purchased from LINGCHANG BIOTECH (China). Mice were divided into four groups: (i) sham, (ii) I/R, (iii) I/R+entacapone, and (iv) I/R + Fer-1. Entacapone (15 mg/kg bodyweight) was dissolved in sodium carboxymethyl cellulose (0.5%) and administered (i.g.) to mice. Mice in the sham group were administered (i.g.) an equal volume of solvent. Fer-1 was dissolved in 5% dimethyl sulfoxide + 30% polyethylene glycol-400 + 60% saline and injected (i.p.). Mice were treated three times per day for 3 days in advance. Before I/R, mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.). The abdomen was exposed and bilateral renal pedicles were clamped to induce renal I/R. After 25 min, the arterial clamps were removed. A body temperature of 37 was maintained throughout the procedure. The sham group underwent the same procedure except for clamping of the renal pedicle. Mice were killed 24 h after reperfusion, and kidney and blood samples were collected for experimentation. Click to Show/Hide
Response regulation	Entacapone upregulates p62 (SQSTM1) expression and affects the p62- KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, ischemia/reperfusion-induced acute kidney injury (I/R-AKI).
Experiment 14 Reporting the Ferroptosis Target of This Regulator				[13]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Chronic kidney disease		ICD-11: GB61	Disease Info
Responsed Drug	Formononetin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model	For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. Click to Show/Hide
Response regulation	Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/ Keap1 complex and enhanced Nrf2 nuclear accumulation.
Experiment 15 Reporting the Ferroptosis Target of This Regulator				[14]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Responsed Drug	Astaxanthin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.
Experiment 16 Reporting the Ferroptosis Target of This Regulator				[15]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Responsed Drug	Panaxydol		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	BEAS-2B cells	Normal	Homo sapiens	CVCL_0168
In Vivo Model	Specific pathogen-free (SPF) male C57BL/6 mice (6-8 weeks old, 20-24 g body weight) were purchased from the Experimental Animal Center, Anhui Medical University (Hefei, China). All mice were randomly divided into five groups (8 mice every group): control group, LPS group, PX+LPS group (administered 20 mg/kg PX), Fe+LPS group (administered 15 mg/kg Fe-citrate (III)), and PX+Fe+LPS group (administered 20 mg/kg PX and 15 mg/kg Fe-citrate (III)). Fe-citrate (III) was dissolved in stroke-physiological saline solution (SPSS). PX was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich), and further diluted in SPSS. Intravenous injection of Fe or/and intraperitoneal injection of PX were performed from day 0 to day 2. At 1 h after the final Fe and PX treatment, the mice were anesthetized with 30 mg/kg of pentobarbital sodium (Beijing Chemical Co., China) and then LPS (10 ug/mouse; InvivoGen, San Diego, CA, USA) or SPSS was injected into the trachea. Click to Show/Hide
Response regulation	Ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and panaxydol (PX) might ameliorate LPS-induced inflammation via inhibiting ferroptosis. PX attenuates ferroptosis against LPS-induced acute lung injury via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for acute lung injury.
Experiment 17 Reporting the Ferroptosis Target of This Regulator				[16]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Injury of intra-abdominal organs		ICD-11: NB91	Disease Info
Responsed Drug	Baicalin		Terminated	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vivo Model	C57BL/6 mice at 6-8 weeks were intraperitoneally injected with D-GalN/LPS (1772-03-8/L2880, Sigma-Aldrich, USA) at a dose of 700 mg/kg and 10 ug/kg, respectively. The constructed D-GaIN/LPS-induced ALI model mice were named the model group, and the normal mice injected with phosphate-buffered saline (PBS) were named the blank group. After 1 h of LPS/D-GalN treatment, Exo and Ba-Exo (150 ug/mice) were injected into the tail vein of the mice in the Exo and Ba-Exo groups, respectively. Mice were sacrificed via anesthesia overdose 12 h after the intervention. Half of the liver tissue was fixed in paraformaldehyde, while the other half was frozen at 80 . Peripheral blood serum was stored at -80 . Click to Show/Hide
Response regulation	Baicalin-pretreated MSCs (Ba-Exo) exerts a protective effect on liver function and activates the Keap1-NRF2 pathway via P62 (SQSTM1), thereby inhibiting ROS production and lipid peroxide-induced ferroptosis. Therefore, baicalin pretreatment is an effective and promising approach in optimizing the therapeutic efficacy of Exo in acute liver injury (ALI).
Experiment 18 Reporting the Ferroptosis Target of This Regulator				[17]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Injury of intra-abdominal organs		ICD-11: NB91	Disease Info
Responsed Drug	Clausenamide		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HepaRG cells	Hepatocellular carcinoma	Homo sapiens	CVCL_9720
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	BEL-7402 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_5492
In Vivo Model	Male C57BL/6 mice aged 8-10 weeks were purchased from Guangdong Experimental Animal Center (Guangzhou, China). The animals were maintained on a 12 h light-dark cycle in a regulated temperature and humidity environment for 1 week before drug administration. (+)-CLA (50 mg/kg/day, i.g.) or fer-1 (2.5 umol/kg/day, i.p.)were administered for 7 consecutive days. To induce liver injury, mice were injected with erastin (100 mg/kg/day, i.p., twice a day) on both the 6th and 7th day, or a single dose of APAP (600 mg/kg/day, i.p.) on the 7th day after overnight food deprivation. The serum and livers were obtained for analysis. Click to Show/Hide
Response regulation	(+)-clausenamide ((+)-CLA) specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability. Thus, (+)-CLA protects against acetaminophen-induced hepatotoxicity via inhibiting ferroptosis and activating the Keap1/Nrf2 pathway in a Cys-151-dependent manner.
Experiment 19 Reporting the Ferroptosis Target of This Regulator				[18]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Injury of intra-abdominal organs		ICD-11: NB91	Disease Info
Responsed Drug	Xiaojianzhong		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hGCs (Gastric cells)
In Vivo Model	C57BL/6 mice (Male, 6-8 weeks old, 20 g± 2 g) were purchased from Chengdu Yaokang Biotechnology Co., Ltd. (Chengdu, China). All animals were housed in the animal room of Shaanxi University ofTraditional Chinese Medicine, at a temperature of 22 ± 2 and a humidity of 40% ± 5%, alternating between light and dark. In the study, the mice were randomly divided into six groups (n = 10 in each group): the blank group, model group,XJZ high dose group, XJZ medium dose group, XJZ low dose group, and positive control (omeprazole) group. The mice in the model group were given Aspirin (300 mg/kg) via gavage for 14 days; the mice in the XJZ high dose group, XJZ medium dose group, and XJZ low dose group were given aspirin (300 mg/kg) by gavage in the morning and three different concentrations (12 g/kg, 6 g/kg, or 3 g/kg) of XJZ decoction by gavage in the afternoon; the mice in the positive control group were given aspirin (300 mg/kg) by gavage in the morning andomeprazole(20 mg/kg) by gavage in the afternoon. After the model was successfully constructed, the mice were anesthetized with isoflurane and gastric tissues were extracted for analysis. Click to Show/Hide
Response regulation	Xiaojianzhong (XJZ) significantly counteracted aspirin-induced gastric mucosal injury and inhibited oxidative stress and ferroptosis in mice. Upon examining SQSTM1/p62(p62)/ Kelch-like ECH-associated protein 1 (Keap1)/Nuclear Factor erythroid 2-Related Factor 2 (Nrf2), a well-known signaling pathway involved in the regulation of oxidative stress and ferroptosis, we found that its activation was significantly inhibited by aspirin treatment and that this signaling pathway was activated after XJZ intervention.
Experiment 20 Reporting the Ferroptosis Target of This Regulator				[20]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RKO cells	Colon carcinoma	Homo sapiens	CVCL_0504
	HCT 116 cells	Colon carcinoma	Homo sapiens	CVCL_0291
	Caco-2 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0025
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
	SW620 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0547
	FHC cells	Normal	Homo sapiens	CVCL_3688
In Vivo Model	To clarify the role of LINC00239 in vivo, we used 4-week-old male BALB/c nude mice provided by the Experimental Animal Center of the Air Force Military Medical University. HCT116 or SW620 cells (1 x 10⁷ cells) were injected subcutaneously into the right flanks of these mice to establish a CRC xenograft model. One week after the injection of cells, the volume of xenografts was continuously monitored (once a week). Four weeks later, the xenografts were removed, and the weights were measured. Click to Show/Hide
Response regulation	LINC00239 plays a novel and indispensable role in ferroptosis by nucleotides 1-315 of LINC00239 to interact with the Kelch domain (Nrf2-binding site) of Keap1, inhibiting Nrf2 ubiquitination and increasing Nrf2 protein stability. And LINC00239 expression has a positive correlation with Nrf2 and GPX4 expression in colorectal cancer tissues. LINC00239 inhibition in combination with ferroptosis induction might be a promising therapeutic strategy for CRC patients.
Experiment 21 Reporting the Ferroptosis Target of This Regulator				[21]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Health		ICD-11: N.A.	Disease Info
Responsed Drug	Calcitriol		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	ZFL cells	Normal	Danio rerio	CVCL_3276
Response regulation	This study confirmed the protective effect of calcitriol on RSL3-induced ferroptosis in zebrafish liver cells, and reported for the first time that calcitriol inhibits ferroptosis in fish cells by regulating the Keap1/Nrf2/GPx4 axis and NF-kB/hepcidin axis.

Heme oxygenase 1 (HMOX1) [Driver; Suppressor]

Target Info

In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[10]
Target for Ferroptosis	Suppressor
Responsed Disease	Degenerative arthritis		ICD-11: FA05	Disease Info
Responsed Drug	Baicalein		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[14]
Target for Ferroptosis	Suppressor
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Responsed Drug	Astaxanthin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.

Unspecific Target [Unspecific Target]

In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[19]
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Responsed Drug	Auriculasin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell invasion
In Vitro Model	HCT 116 cells	Colon carcinoma	Homo sapiens	CVCL_0291
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
Response regulation	Auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1. AC can promote colorectal cancer cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and colony formation, indicating that AC has a significant tumor suppressor effect.

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	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Apatinib		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/ Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Apatinib		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.

Hepatocellular carcinoma [ICD-11: 2C12]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Tiliroside		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 10⁶ HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm³, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde. Click to Show/Hide
Response regulation	Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[3]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Withaferin A		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
	Cell adhesion molecules			hsa04514
Cell Process	Cell ferroptosis
	Cell proliferation
	Cell invasion
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	SNU-449 cells	Adult hepatocellular carcinoma	Homo sapiens	CVCL_0454
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
Response regulation	Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for Hepatocellular carcinoma therapy, especially for advanced hepatocellular carcinoma.

Melanoma [ICD-11: 2C30]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[4]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Nobiletin		Investigative	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	SK-MEL-28 cells	Cutaneous melanoma	Homo sapiens	CVCL_0526
Response regulation	Nobiletin could induce ferroptosis by regulating the GSK3B-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.

Vascular dementia [ICD-11: 6D81]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[5]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Gastrodin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Male Sprague-Dawley rats (weight 260 ± 20 g; Guizhou Medical University Experimental Animal Center; Certificate No. SCXK2018-0001; Grant No. 2200483) were reared in a specific pathogen-free environment with 12 h light/dark cycle and 55% ± 10% humidity at a temperature of 20~25 , were provided with sufficient feed and sterile drinking water and fasted for 6 h before and after surgery. All animal experiments were performed in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. Click to Show/Hide
Response regulation	Gastrodin (GAS) inhibited ferroptosis in hippocampal neurons by activating the Nrf2/ Keap1-GPx4 signaling pathway, suggesting its possible application as a functional food for improving vascular dementia by inhibiting ferroptosis.

Parkinson disease [ICD-11: 8A00]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[6]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	L. lactis MG1363-pMG36e-GLP-1	Investigative	Drug Info
Pathway Response	Pathways in cancer		hsa05200
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Colon tissues (Mouse colon tissues)
	hBCs (Brain cells)
In Vivo Model	Fifty male C57BL/6 mice provided by Hunan SJA Laboratory Animal Co., Ltd. (Changsha, China) resided in an animal house (temperature 26 ± 1 , humidity 50 ± 10%), in which the light was on for 12 h and off for 12 h. Mice were acclimatised for 1 week and allowed water and animal food with no limitations. Then, all mice were stochastically divided into 5 groups using random number tables available online (https://www.random-online.com/, accessed on 26 December 2021), including: (1) C group, a control group treated with normal saline for 7 consecutive days (n = 10); (2) M group, a model group with intraperitoneal injection of 20 mg/kg/day MPTP (Sigma-Aldrich, Taufkirchen, Germany, M0896) for 7 consecutive days (n = 10); (3) L group, treated with MPTP and 0.4 mg/kg/day liraglutide for 7 consecutive days (n = 10); (4) R group, treated with MPTP and 109 colony-forming unit (CFU) L. lactis MG1363 for 7 consecutive days via gavage (n = 10); (5) RG group, treated with MPTP and 109 CFUL. lactis MG1363-pMG36e-GLP-1 for 7 consecutive days via gavage (n = 10). All animals survived treatment and all animal experiments were administered from 9:00 to 12:00 in the morning to reduce systematic errors. Click to Show/Hide
Response regulation	L. lactis MG1363-pMG36e-GLP-1 exerts neurotrophic effects via activating the Keap1/Nrf2/GPX4 signalling pathway to down-regulate ACSL4 and up-regulate FSP1 to suppress ferroptosis. These results indicated that the neurotrophic effects of the next-generation probiotics L. lactis MG1363-pMG36e-GLP-1 against MPTP-induced Parkinsonism are mediated by modulating oxidative stress, inhibiting ferroptosis, and redressing dysbiosis.

Subarachnoid Hemorrhage [ICD-11: 8B01]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[7]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	Astragaloside IV	Investigative	Drug Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hBCs (Brain cells)
In Vivo Model	SAH model was constructed by applying endovascular perforation in the rats, according to the protocol introduced in a previous study (Wei et al., 2020), except for slight modifications. Briefly, after performing intraperitoneal anesthesia with 40 mg/kg sodium pentobarbital, the right common carotid, external and internal carotid arteries of the rats were exposed and isolated. The right external carotid artery was ligated, and a 4-0 single-strand nylon thread was used to insert the right internal carotid artery through the stump of the external carotid artery and the bifurcation of the common carotid artery. When resistance is felt when the suture enters the intracranial segment, proceed approximately 3 mm to penetrate internal carotid artery at the bifurcation of middle cerebral artery. The suture was held in this position for 10 s and was then withdrawn. The rats in the Sham group went through an identical procedure, without the suture at the point of resistance. Throughout the experiment, the body temperature of the rats was sustained at around 37 by using a thermal blanket. After the wounds were sutured, the rats were placed in a separate cage and neurological function was closely observed. Click to Show/Hide
Response regulation	Astragaloside IV (AS-IV) triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of subarachnoid hemorrhage (SAH). The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. Ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway. The liberation of Nrf2 from Keap1, its cytoplasmic repressor will provoke Nrf2 accumulation in the nucleus.

Cerebral ischemia [ICD-11: 8B10]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[8]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Astragaloside IV		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	SH-SY5Y cells	Neuroblastoma	Homo sapiens	CVCL_0019
In Vivo Model	Rats were randomly divided into the Sham, middle cerebral artery occlusion-reperfusion (MCAO/R), and MCAO/R + AST IV (28 mg/kg) groups. The MCAO/R + AST IV group was intragastrically injected with 10 mL/kg AST IV at 50, 26, and 2 h before modelling (Xiao et al., 2021). The Sham and MCAO/R groups received equal amounts of normal saline. As described previously, the modified Longa method (Longa et al., 1989) was used to establish the MCAO/R model. After anaesthesia with 2%sodium pentobarbital, the left common carotid artery(CCA), the external carotid artery(ECA), and the internal carotid artery(ICA) were isolated. The distal end of the ECA was ligated, a small incision was made at the stump of the ECA, and a suture (Batch number: 2636A2, Beijing Seinong Technology Co., Ltd., Beijing, China; head-end diameter: 0.36 ± 0.02 mm) was inserted into the ICA from the ECA through the bifurcation of the CCA. To achieve cerebral ischaemia, the head-end was used to block blood flow in the middle cerebral artery until the intracranial segment of the ICA was inserted. The suture was removed after 2 h, and follow-up experiments were performed 24 h after reperfusion. In the Sham group, the CCA, ECA, and ICA were exposed and separated, but no sutures were inserted. Penicillin powder was used to fight infection after operation. Click to Show/Hide
Response regulation	Astragaloside IV (AST IV) increased the P62 (SQSTM1) and Nrf2 levels and decreased the Keap1 levels. P62 silencing reduced the effects of AST IV on the P62/ Keap1/Nrf2 pathway and ferroptosis. Our findings suggest that AST IV mitigates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via activation of the P62/ Keap1/Nrf2 pathway.

Nonalcoholic fatty liver disease [ICD-11: DB92]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[9]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Dehydroabietic acid		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HEK-293T cells	Normal	Homo sapiens	CVCL_0063
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	The male C57BL/6J mice (6-8 weeks, Beijing Vital River Laboratory Animal Technology Co., Ltd., China) were exposed to 12 h of light and darkness at temperature (22 ± 2 ), humidity (55%) with free access to water and food. All the mice were acclimated for 1 week before the experiment, then the mice were fed normal chow diet (NCD) and high-fat diet (HFD, D12492) for 12 weeks. The HFD group was divided into 3 groups (HFD, low dose of DA (DA-L, 10 mg/kg/d), high dose of DA (DA-H, 20 mg/kg/d),n = 8)). DA was administered by gavage for 9 weeks, and 0.5% CMC-Na was administered by NCD and HFD. Click to Show/Hide
Response regulation	Dehydroabietic acid (DA) inhibited ferroptosis and increased the expression of key genes such as ferroptosis suppressor protein 1 (FSP1) in vitro and vivo. In all, DA may bind with Keap1, activate Nrf2-ARE, induce its target gene expression, inhibit ROS accumulation and lipid peroxidation, and reduce HFD-induced nonalcoholic fatty liver disease (NAFLD).

Degenerative arthritis [ICD-11: FA05]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[10]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	Baicalein	Investigative	Drug Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation
Experiment 2 Reporting the Ferroptosis-centered Disease Response			[10]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	Baicalein	Investigative	Drug Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation

Endometrial hyperplasia [ICD-11: GA16]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[11]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	Guizhi Fuling Capsule	Investigative	Drug Info
Pathway Response	Fatty acid metabolism		hsa01212
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	mUTs (Mouse uterine tissues)
In Vivo Model	Female C57BL/6 mice (8-week-old) were purchased from Model Animal Research Center of Nanjing University (Nanjing, China). Fifteen mice were randomly divided into three groups: Olive oil group, Estradiol group and Estradiol + IKE group. The Estradiol group was subcutaneously injected estradiol (50 ug/kg/day), Estradiol + IKE group was subcutaneously injected estradiol and intraperitoneally injected IKE (50 mg/kg) for 21 days, while the Olive oil group received the same volume of olive oil. In the experiment of exploring the improvement of GFC to EH, twenty mice were randomly divided into four groups: Olive oil group, Estradiol group, 75 mg/kg GFC group and 150 mg/kg GFC group. Except for Olive oil group, mice were subcutaneously daily injected with estradiol (50 ug/kg/day) for 21 days, while the Olive oil group received the same volume of olive oil. 75 mg/kg GFC group and 150 mg/kg GFC group were treated with GFC intragastrical administration. Click to Show/Hide
Response regulation	Guizhi Fuling Capsule (GFC) may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62 (SQSTM1)- Keap1-NRF2 pathway. GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.

Acute kidney failure [ICD-11: GB60]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[12]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Entacapone		Approved	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HK-2 cells	Normal	Homo sapiens	CVCL_0302
In Vivo Model	Male C57BL/6 mice (8-10 weeks; 20-25 g) were purchased from LINGCHANG BIOTECH (China). Mice were divided into four groups: (i) sham, (ii) I/R, (iii) I/R+entacapone, and (iv) I/R + Fer-1. Entacapone (15 mg/kg bodyweight) was dissolved in sodium carboxymethyl cellulose (0.5%) and administered (i.g.) to mice. Mice in the sham group were administered (i.g.) an equal volume of solvent. Fer-1 was dissolved in 5% dimethyl sulfoxide + 30% polyethylene glycol-400 + 60% saline and injected (i.p.). Mice were treated three times per day for 3 days in advance. Before I/R, mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.). The abdomen was exposed and bilateral renal pedicles were clamped to induce renal I/R. After 25 min, the arterial clamps were removed. A body temperature of 37 was maintained throughout the procedure. The sham group underwent the same procedure except for clamping of the renal pedicle. Mice were killed 24 h after reperfusion, and kidney and blood samples were collected for experimentation. Click to Show/Hide
Response regulation	Entacapone upregulates p62 (SQSTM1) expression and affects the p62- KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, ischemia/reperfusion-induced acute kidney injury (I/R-AKI).

Chronic kidney disease [ICD-11: GB61]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[13]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)	Protein coding	Regulator Info
Responsed Drug	Formononetin	Investigative	Drug Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model	For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. Click to Show/Hide
Response regulation	Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/ Keap1 complex and enhanced Nrf2 nuclear accumulation.

Lung injury [ICD-11: NB32]

Disease Info

In total 3 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[14]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Astaxanthin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[15]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Panaxydol		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	BEAS-2B cells	Normal	Homo sapiens	CVCL_0168
In Vivo Model	Specific pathogen-free (SPF) male C57BL/6 mice (6-8 weeks old, 20-24 g body weight) were purchased from the Experimental Animal Center, Anhui Medical University (Hefei, China). All mice were randomly divided into five groups (8 mice every group): control group, LPS group, PX+LPS group (administered 20 mg/kg PX), Fe+LPS group (administered 15 mg/kg Fe-citrate (III)), and PX+Fe+LPS group (administered 20 mg/kg PX and 15 mg/kg Fe-citrate (III)). Fe-citrate (III) was dissolved in stroke-physiological saline solution (SPSS). PX was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich), and further diluted in SPSS. Intravenous injection of Fe or/and intraperitoneal injection of PX were performed from day 0 to day 2. At 1 h after the final Fe and PX treatment, the mice were anesthetized with 30 mg/kg of pentobarbital sodium (Beijing Chemical Co., China) and then LPS (10 ug/mouse; InvivoGen, San Diego, CA, USA) or SPSS was injected into the trachea. Click to Show/Hide
Response regulation	Ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and panaxydol (PX) might ameliorate LPS-induced inflammation via inhibiting ferroptosis. PX attenuates ferroptosis against LPS-induced acute lung injury via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for acute lung injury.
Experiment 3 Reporting the Ferroptosis-centered Disease Response				[14]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Astaxanthin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.

Injury of intra-abdominal organs [ICD-11: NB91]

Disease Info

In total 3 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[16]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Baicalin		Terminated	Drug Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vivo Model	C57BL/6 mice at 6-8 weeks were intraperitoneally injected with D-GalN/LPS (1772-03-8/L2880, Sigma-Aldrich, USA) at a dose of 700 mg/kg and 10 ug/kg, respectively. The constructed D-GaIN/LPS-induced ALI model mice were named the model group, and the normal mice injected with phosphate-buffered saline (PBS) were named the blank group. After 1 h of LPS/D-GalN treatment, Exo and Ba-Exo (150 ug/mice) were injected into the tail vein of the mice in the Exo and Ba-Exo groups, respectively. Mice were sacrificed via anesthesia overdose 12 h after the intervention. Half of the liver tissue was fixed in paraformaldehyde, while the other half was frozen at 80 . Peripheral blood serum was stored at -80 . Click to Show/Hide
Response regulation	Baicalin-pretreated MSCs (Ba-Exo) exerts a protective effect on liver function and activates the Keap1-NRF2 pathway via P62 (SQSTM1), thereby inhibiting ROS production and lipid peroxide-induced ferroptosis. Therefore, baicalin pretreatment is an effective and promising approach in optimizing the therapeutic efficacy of Exo in acute liver injury (ALI).
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[17]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Clausenamide		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HepaRG cells	Hepatocellular carcinoma	Homo sapiens	CVCL_9720
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	BEL-7402 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_5492
In Vivo Model	Male C57BL/6 mice aged 8-10 weeks were purchased from Guangdong Experimental Animal Center (Guangzhou, China). The animals were maintained on a 12 h light-dark cycle in a regulated temperature and humidity environment for 1 week before drug administration. (+)-CLA (50 mg/kg/day, i.g.) or fer-1 (2.5 umol/kg/day, i.p.)were administered for 7 consecutive days. To induce liver injury, mice were injected with erastin (100 mg/kg/day, i.p., twice a day) on both the 6th and 7th day, or a single dose of APAP (600 mg/kg/day, i.p.) on the 7th day after overnight food deprivation. The serum and livers were obtained for analysis. Click to Show/Hide
Response regulation	(+)-clausenamide ((+)-CLA) specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability. Thus, (+)-CLA protects against acetaminophen-induced hepatotoxicity via inhibiting ferroptosis and activating the Keap1/Nrf2 pathway in a Cys-151-dependent manner.
Experiment 3 Reporting the Ferroptosis-centered Disease Response				[18]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Xiaojianzhong		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hGCs (Gastric cells)
In Vivo Model	C57BL/6 mice (Male, 6-8 weeks old, 20 g± 2 g) were purchased from Chengdu Yaokang Biotechnology Co., Ltd. (Chengdu, China). All animals were housed in the animal room of Shaanxi University ofTraditional Chinese Medicine, at a temperature of 22 ± 2 and a humidity of 40% ± 5%, alternating between light and dark. In the study, the mice were randomly divided into six groups (n = 10 in each group): the blank group, model group,XJZ high dose group, XJZ medium dose group, XJZ low dose group, and positive control (omeprazole) group. The mice in the model group were given Aspirin (300 mg/kg) via gavage for 14 days; the mice in the XJZ high dose group, XJZ medium dose group, and XJZ low dose group were given aspirin (300 mg/kg) by gavage in the morning and three different concentrations (12 g/kg, 6 g/kg, or 3 g/kg) of XJZ decoction by gavage in the afternoon; the mice in the positive control group were given aspirin (300 mg/kg) by gavage in the morning andomeprazole(20 mg/kg) by gavage in the afternoon. After the model was successfully constructed, the mice were anesthetized with isoflurane and gastric tissues were extracted for analysis. Click to Show/Hide
Response regulation	Xiaojianzhong (XJZ) significantly counteracted aspirin-induced gastric mucosal injury and inhibited oxidative stress and ferroptosis in mice. Upon examining SQSTM1/p62(p62)/ Kelch-like ECH-associated protein 1 (Keap1)/Nuclear Factor erythroid 2-Related Factor 2 (Nrf2), a well-known signaling pathway involved in the regulation of oxidative stress and ferroptosis, we found that its activation was significantly inhibited by aspirin treatment and that this signaling pathway was activated after XJZ intervention.

Colorectal cancer [ICD-11: 2B91]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[19]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Auriculasin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell invasion
In Vitro Model	HCT 116 cells	Colon carcinoma	Homo sapiens	CVCL_0291
In Vitro Model	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
Response regulation	Auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1. AC can promote colorectal cancer cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and colony formation, indicating that AC has a significant tumor suppressor effect.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[20]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Pathway Response	Pathways in cancer			hsa05200
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RKO cells	Colon carcinoma	Homo sapiens	CVCL_0504
	HCT 116 cells	Colon carcinoma	Homo sapiens	CVCL_0291
	Caco-2 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0025
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
	SW620 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0547
	FHC cells	Normal	Homo sapiens	CVCL_3688
In Vivo Model	To clarify the role of LINC00239 in vivo, we used 4-week-old male BALB/c nude mice provided by the Experimental Animal Center of the Air Force Military Medical University. HCT116 or SW620 cells (1 x 10⁷ cells) were injected subcutaneously into the right flanks of these mice to establish a CRC xenograft model. One week after the injection of cells, the volume of xenografts was continuously monitored (once a week). Four weeks later, the xenografts were removed, and the weights were measured. Click to Show/Hide
Response regulation	LINC00239 plays a novel and indispensable role in ferroptosis by nucleotides 1-315 of LINC00239 to interact with the Kelch domain (Nrf2-binding site) of Keap1, inhibiting Nrf2 ubiquitination and increasing Nrf2 protein stability. And LINC00239 expression has a positive correlation with Nrf2 and GPX4 expression in colorectal cancer tissues. LINC00239 inhibition in combination with ferroptosis induction might be a promising therapeutic strategy for CRC patients.

Health [ICD-11: N.A.]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[21]
Target Regulator	Kelch-like ECH-associated protein 1 (KEAP1)		Protein coding	Regulator Info
Responsed Drug	Calcitriol		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	ZFL cells	Normal	Danio rerio	CVCL_3276
Response regulation	This study confirmed the protective effect of calcitriol on RSL3-induced ferroptosis in zebrafish liver cells, and reported for the first time that calcitriol inhibits ferroptosis in fish cells by regulating the Keap1/Nrf2/GPx4 axis and NF-kB/hepcidin axis.

Entacapone [Approved]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[12]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Acute kidney failure		ICD-11: GB60	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HK-2 cells	Normal	Homo sapiens	CVCL_0302
In Vivo Model	Male C57BL/6 mice (8-10 weeks; 20-25 g) were purchased from LINGCHANG BIOTECH (China). Mice were divided into four groups: (i) sham, (ii) I/R, (iii) I/R+entacapone, and (iv) I/R + Fer-1. Entacapone (15 mg/kg bodyweight) was dissolved in sodium carboxymethyl cellulose (0.5%) and administered (i.g.) to mice. Mice in the sham group were administered (i.g.) an equal volume of solvent. Fer-1 was dissolved in 5% dimethyl sulfoxide + 30% polyethylene glycol-400 + 60% saline and injected (i.p.). Mice were treated three times per day for 3 days in advance. Before I/R, mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.). The abdomen was exposed and bilateral renal pedicles were clamped to induce renal I/R. After 25 min, the arterial clamps were removed. A body temperature of 37 was maintained throughout the procedure. The sham group underwent the same procedure except for clamping of the renal pedicle. Mice were killed 24 h after reperfusion, and kidney and blood samples were collected for experimentation. Click to Show/Hide
Response regulation	Entacapone upregulates p62 (SQSTM1) expression and affects the p62- KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, ischemia/reperfusion-induced acute kidney injury (I/R-AKI).

Astragaloside IV [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[7]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Subarachnoid Hemorrhage		ICD-11: 8B01	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hBCs (Brain cells)
In Vivo Model	SAH model was constructed by applying endovascular perforation in the rats, according to the protocol introduced in a previous study (Wei et al., 2020), except for slight modifications. Briefly, after performing intraperitoneal anesthesia with 40 mg/kg sodium pentobarbital, the right common carotid, external and internal carotid arteries of the rats were exposed and isolated. The right external carotid artery was ligated, and a 4-0 single-strand nylon thread was used to insert the right internal carotid artery through the stump of the external carotid artery and the bifurcation of the common carotid artery. When resistance is felt when the suture enters the intracranial segment, proceed approximately 3 mm to penetrate internal carotid artery at the bifurcation of middle cerebral artery. The suture was held in this position for 10 s and was then withdrawn. The rats in the Sham group went through an identical procedure, without the suture at the point of resistance. Throughout the experiment, the body temperature of the rats was sustained at around 37 by using a thermal blanket. After the wounds were sutured, the rats were placed in a separate cage and neurological function was closely observed. Click to Show/Hide
Response regulation	Astragaloside IV (AS-IV) triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of subarachnoid hemorrhage (SAH). The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. Ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway. The liberation of Nrf2 from Keap1, its cytoplasmic repressor will provoke Nrf2 accumulation in the nucleus.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[8]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Cerebral ischemia		ICD-11: 8B10	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	SH-SY5Y cells	Neuroblastoma	Homo sapiens	CVCL_0019
In Vivo Model	Rats were randomly divided into the Sham, middle cerebral artery occlusion-reperfusion (MCAO/R), and MCAO/R + AST IV (28 mg/kg) groups. The MCAO/R + AST IV group was intragastrically injected with 10 mL/kg AST IV at 50, 26, and 2 h before modelling (Xiao et al., 2021). The Sham and MCAO/R groups received equal amounts of normal saline. As described previously, the modified Longa method (Longa et al., 1989) was used to establish the MCAO/R model. After anaesthesia with 2%sodium pentobarbital, the left common carotid artery(CCA), the external carotid artery(ECA), and the internal carotid artery(ICA) were isolated. The distal end of the ECA was ligated, a small incision was made at the stump of the ECA, and a suture (Batch number: 2636A2, Beijing Seinong Technology Co., Ltd., Beijing, China; head-end diameter: 0.36 ± 0.02 mm) was inserted into the ICA from the ECA through the bifurcation of the CCA. To achieve cerebral ischaemia, the head-end was used to block blood flow in the middle cerebral artery until the intracranial segment of the ICA was inserted. The suture was removed after 2 h, and follow-up experiments were performed 24 h after reperfusion. In the Sham group, the CCA, ECA, and ICA were exposed and separated, but no sutures were inserted. Penicillin powder was used to fight infection after operation. Click to Show/Hide
Response regulation	Astragaloside IV (AST IV) increased the P62 (SQSTM1) and Nrf2 levels and decreased the Keap1 levels. P62 silencing reduced the effects of AST IV on the P62/ Keap1/Nrf2 pathway and ferroptosis. Our findings suggest that AST IV mitigates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via activation of the P62/ Keap1/Nrf2 pathway.

Tiliroside [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	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 10⁶ HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm³, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde. Click to Show/Hide
Response regulation	Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.

Withaferin A [Investigative]

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	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
	Cell adhesion molecules			hsa04514
Cell Process	Cell ferroptosis
	Cell proliferation
	Cell invasion
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	SNU-449 cells	Adult hepatocellular carcinoma	Homo sapiens	CVCL_0454
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
Response regulation	Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for Hepatocellular carcinoma therapy, especially for advanced hepatocellular carcinoma.

Baicalin [Terminated]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[16]
Drug for Ferroptosis	Inducer
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Injury of intra-abdominal organs	ICD-11: NB91	Disease Info
Pathway Response	Pathways in cancer		hsa05200
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vivo Model	C57BL/6 mice at 6-8 weeks were intraperitoneally injected with D-GalN/LPS (1772-03-8/L2880, Sigma-Aldrich, USA) at a dose of 700 mg/kg and 10 ug/kg, respectively. The constructed D-GaIN/LPS-induced ALI model mice were named the model group, and the normal mice injected with phosphate-buffered saline (PBS) were named the blank group. After 1 h of LPS/D-GalN treatment, Exo and Ba-Exo (150 ug/mice) were injected into the tail vein of the mice in the Exo and Ba-Exo groups, respectively. Mice were sacrificed via anesthesia overdose 12 h after the intervention. Half of the liver tissue was fixed in paraformaldehyde, while the other half was frozen at 80 . Peripheral blood serum was stored at -80 . Click to Show/Hide
Response regulation	Baicalin-pretreated MSCs (Ba-Exo) exerts a protective effect on liver function and activates the Keap1-NRF2 pathway via P62 (SQSTM1), thereby inhibiting ROS production and lipid peroxide-induced ferroptosis. Therefore, baicalin pretreatment is an effective and promising approach in optimizing the therapeutic efficacy of Exo in acute liver injury (ALI).

Apatinib [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	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/ Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
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	Pathways in cancer			hsa05200
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used. Click to Show/Hide
Response regulation	Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.

Astaxanthin [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[14]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[14]
Drug for Ferroptosis	Suppressor
Response Target	Heme oxygenase 1 (HMOX1)		Driver; Suppressor	Target Info
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	RAW 264.7 cells	Leukemia	Mus musculus	CVCL_0493
In Vivo Model	6-week-Babl/c female mice were randomized to the following three groups of seven mice each: vehicle group, LPS group, Astaxanthin plus LPS group. Astaxanthin plus LPS group mice were pretreated with astaxanthin (20 mg/kg) byi.v injectionfor daily for 7 consecutive days. Astaxanthin was dissolved in 2%DMSO (vol/vol), 40% PEG-400 (vol/vol), 2% Tween 80 (vol/vol), and 56% PBS (vol/vol). On the last day, the mice were intraperitoneally injected with 5 mg/kg LPS or normal saline 2 h after the injection of astaxanthin. After 6 h of LPS stimulation, mice were euthanized to collect the BALF, and lung tissue samples. BALF was collected three times through a tracheal cannula with autoclaved normal saline, instilled up to a total volume of 1.8 ml. Click to Show/Hide
Response regulation	Astaxanthin protected LPS-induced cell inflammation and acute lung injury (ALI) in mice by inhibiting ferroptosis, and its effect was achieved through Keap1-Nrf2/HO-1 pathway. Therefore, our study indicates that ferroptosis will become a new target for the treatment of ALI, and astaxanthin is a potential drug for the treatment of ALI.

Baicalein [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[10]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Degenerative arthritis	ICD-11: FA05	Disease Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation
Experiment 2 Reporting the Ferroptosis-centered Drug Response			[10]
Drug for Ferroptosis	Suppressor
Response Target	Heme oxygenase 1 (HMOX1)	Driver; Suppressor	Target Info
Responsed Disease	Degenerative arthritis	ICD-11: FA05	Disease Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	C57BL/6J (WT) mice (8 weeks old, male) were purchased from Nanjing Medical university, and AMPK-KO mice were purchased from Shanghai Model Organisms. They were used to create an OA model by destabilization of the medial meniscus surgery (DMM) (n = 6 per group). Briefly, after the mice were anaesthetized, a medial articular incision was made to expose the leftjoint cavity, and then the tibial collateral ligament was transected. Finally, the articular incision was closed. In the control group, only the joint cavity was opened. One week after surgery, 1 mg/kg baicalein (MCE, HY-N0196) per knee, 1 mg/kg ML385 (MCE, HY-100523) per knee, 1 mg/kg AICAR (MCE, HY-13417) per knee or 1 mg/kg of the ferroptosis inhibitor ferrostatin-1 (Fer-1, MCE, HY-100579) was injected into the joint cavity of the mice once a week. Meanwhile, saline was injected into the control group. Mice were sacrificed after surgery 10 weeks. Click to Show/Hide
Response regulation	Baicalein alleviated osteoarthritis (OA) development by improving the activity of AMPKa/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA. AMPKa preserved Nrf2 abundance in chondrocytes and promoted Nrf2 into nucleus by promoting Keap1 degradation

Clausenamide [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[17]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Injury of intra-abdominal organs		ICD-11: NB91	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HepaRG cells	Hepatocellular carcinoma	Homo sapiens	CVCL_9720
	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	BEL-7402 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_5492
In Vivo Model	Male C57BL/6 mice aged 8-10 weeks were purchased from Guangdong Experimental Animal Center (Guangzhou, China). The animals were maintained on a 12 h light-dark cycle in a regulated temperature and humidity environment for 1 week before drug administration. (+)-CLA (50 mg/kg/day, i.g.) or fer-1 (2.5 umol/kg/day, i.p.)were administered for 7 consecutive days. To induce liver injury, mice were injected with erastin (100 mg/kg/day, i.p., twice a day) on both the 6th and 7th day, or a single dose of APAP (600 mg/kg/day, i.p.) on the 7th day after overnight food deprivation. The serum and livers were obtained for analysis. Click to Show/Hide
Response regulation	(+)-clausenamide ((+)-CLA) specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability. Thus, (+)-CLA protects against acetaminophen-induced hepatotoxicity via inhibiting ferroptosis and activating the Keap1/Nrf2 pathway in a Cys-151-dependent manner.

Dehydroabietic acid [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[9]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Nonalcoholic fatty liver disease		ICD-11: DB92	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	HEK-293T cells	Normal	Homo sapiens	CVCL_0063
	L-02 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_6926
In Vivo Model	The male C57BL/6J mice (6-8 weeks, Beijing Vital River Laboratory Animal Technology Co., Ltd., China) were exposed to 12 h of light and darkness at temperature (22 ± 2 ), humidity (55%) with free access to water and food. All the mice were acclimated for 1 week before the experiment, then the mice were fed normal chow diet (NCD) and high-fat diet (HFD, D12492) for 12 weeks. The HFD group was divided into 3 groups (HFD, low dose of DA (DA-L, 10 mg/kg/d), high dose of DA (DA-H, 20 mg/kg/d),n = 8)). DA was administered by gavage for 9 weeks, and 0.5% CMC-Na was administered by NCD and HFD. Click to Show/Hide
Response regulation	Dehydroabietic acid (DA) inhibited ferroptosis and increased the expression of key genes such as ferroptosis suppressor protein 1 (FSP1) in vitro and vivo. In all, DA may bind with Keap1, activate Nrf2-ARE, induce its target gene expression, inhibit ROS accumulation and lipid peroxidation, and reduce HFD-induced nonalcoholic fatty liver disease (NAFLD).

Formononetin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[13]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Chronic kidney disease	ICD-11: GB61	Disease Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model	For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. Click to Show/Hide
Response regulation	Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/ Keap1 complex and enhanced Nrf2 nuclear accumulation.

Gastrodin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[5]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Vascular dementia		ICD-11: 6D81	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Male Sprague-Dawley rats (weight 260 ± 20 g; Guizhou Medical University Experimental Animal Center; Certificate No. SCXK2018-0001; Grant No. 2200483) were reared in a specific pathogen-free environment with 12 h light/dark cycle and 55% ± 10% humidity at a temperature of 20~25 , were provided with sufficient feed and sterile drinking water and fasted for 6 h before and after surgery. All animal experiments were performed in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. Click to Show/Hide
Response regulation	Gastrodin (GAS) inhibited ferroptosis in hippocampal neurons by activating the Nrf2/ Keap1-GPx4 signaling pathway, suggesting its possible application as a functional food for improving vascular dementia by inhibiting ferroptosis.

Guizhi Fuling Capsule [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[11]
Drug for Ferroptosis	Inducer
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Endometrial hyperplasia	ICD-11: GA16	Disease Info
Pathway Response	Fatty acid metabolism		hsa01212
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	mUTs (Mouse uterine tissues)
In Vivo Model	Female C57BL/6 mice (8-week-old) were purchased from Model Animal Research Center of Nanjing University (Nanjing, China). Fifteen mice were randomly divided into three groups: Olive oil group, Estradiol group and Estradiol + IKE group. The Estradiol group was subcutaneously injected estradiol (50 ug/kg/day), Estradiol + IKE group was subcutaneously injected estradiol and intraperitoneally injected IKE (50 mg/kg) for 21 days, while the Olive oil group received the same volume of olive oil. In the experiment of exploring the improvement of GFC to EH, twenty mice were randomly divided into four groups: Olive oil group, Estradiol group, 75 mg/kg GFC group and 150 mg/kg GFC group. Except for Olive oil group, mice were subcutaneously daily injected with estradiol (50 ug/kg/day) for 21 days, while the Olive oil group received the same volume of olive oil. 75 mg/kg GFC group and 150 mg/kg GFC group were treated with GFC intragastrical administration. Click to Show/Hide
Response regulation	Guizhi Fuling Capsule (GFC) may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62 (SQSTM1)- Keap1-NRF2 pathway. GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.

L. lactis MG1363-pMG36e-GLP-1 [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[6]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Parkinson disease	ICD-11: 8A00	Disease Info
Pathway Response	Pathways in cancer		hsa05200
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Colon tissues (Mouse colon tissues)
	hBCs (Brain cells)
In Vivo Model	Fifty male C57BL/6 mice provided by Hunan SJA Laboratory Animal Co., Ltd. (Changsha, China) resided in an animal house (temperature 26 ± 1 , humidity 50 ± 10%), in which the light was on for 12 h and off for 12 h. Mice were acclimatised for 1 week and allowed water and animal food with no limitations. Then, all mice were stochastically divided into 5 groups using random number tables available online (https://www.random-online.com/, accessed on 26 December 2021), including: (1) C group, a control group treated with normal saline for 7 consecutive days (n = 10); (2) M group, a model group with intraperitoneal injection of 20 mg/kg/day MPTP (Sigma-Aldrich, Taufkirchen, Germany, M0896) for 7 consecutive days (n = 10); (3) L group, treated with MPTP and 0.4 mg/kg/day liraglutide for 7 consecutive days (n = 10); (4) R group, treated with MPTP and 109 colony-forming unit (CFU) L. lactis MG1363 for 7 consecutive days via gavage (n = 10); (5) RG group, treated with MPTP and 109 CFUL. lactis MG1363-pMG36e-GLP-1 for 7 consecutive days via gavage (n = 10). All animals survived treatment and all animal experiments were administered from 9:00 to 12:00 in the morning to reduce systematic errors. Click to Show/Hide
Response regulation	L. lactis MG1363-pMG36e-GLP-1 exerts neurotrophic effects via activating the Keap1/Nrf2/GPX4 signalling pathway to down-regulate ACSL4 and up-regulate FSP1 to suppress ferroptosis. These results indicated that the neurotrophic effects of the next-generation probiotics L. lactis MG1363-pMG36e-GLP-1 against MPTP-induced Parkinsonism are mediated by modulating oxidative stress, inhibiting ferroptosis, and redressing dysbiosis.

Nobiletin [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	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Melanoma		ICD-11: 2C30	Disease Info
Pathway Response	Pathways in cancer			hsa05200
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	SK-MEL-28 cells	Cutaneous melanoma	Homo sapiens	CVCL_0526
Response regulation	Nobiletin could induce ferroptosis by regulating the GSK3B-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.

Panaxydol [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[15]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Lung injury		ICD-11: NB32	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
Cell Process	Cell ferroptosis
In Vitro Model	BEAS-2B cells	Normal	Homo sapiens	CVCL_0168
In Vivo Model	Specific pathogen-free (SPF) male C57BL/6 mice (6-8 weeks old, 20-24 g body weight) were purchased from the Experimental Animal Center, Anhui Medical University (Hefei, China). All mice were randomly divided into five groups (8 mice every group): control group, LPS group, PX+LPS group (administered 20 mg/kg PX), Fe+LPS group (administered 15 mg/kg Fe-citrate (III)), and PX+Fe+LPS group (administered 20 mg/kg PX and 15 mg/kg Fe-citrate (III)). Fe-citrate (III) was dissolved in stroke-physiological saline solution (SPSS). PX was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich), and further diluted in SPSS. Intravenous injection of Fe or/and intraperitoneal injection of PX were performed from day 0 to day 2. At 1 h after the final Fe and PX treatment, the mice were anesthetized with 30 mg/kg of pentobarbital sodium (Beijing Chemical Co., China) and then LPS (10 ug/mouse; InvivoGen, San Diego, CA, USA) or SPSS was injected into the trachea. Click to Show/Hide
Response regulation	Ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and panaxydol (PX) might ameliorate LPS-induced inflammation via inhibiting ferroptosis. PX attenuates ferroptosis against LPS-induced acute lung injury via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for acute lung injury.

Xiaojianzhong [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[18]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)	Suppressor; Marker	Target Info
Responsed Disease	Injury of intra-abdominal organs	ICD-11: NB91	Disease Info
Pathway Response	Ferroptosis		hsa04216
	Fatty acid metabolism		hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	hGCs (Gastric cells)
In Vivo Model	C57BL/6 mice (Male, 6-8 weeks old, 20 g± 2 g) were purchased from Chengdu Yaokang Biotechnology Co., Ltd. (Chengdu, China). All animals were housed in the animal room of Shaanxi University ofTraditional Chinese Medicine, at a temperature of 22 ± 2 and a humidity of 40% ± 5%, alternating between light and dark. In the study, the mice were randomly divided into six groups (n = 10 in each group): the blank group, model group,XJZ high dose group, XJZ medium dose group, XJZ low dose group, and positive control (omeprazole) group. The mice in the model group were given Aspirin (300 mg/kg) via gavage for 14 days; the mice in the XJZ high dose group, XJZ medium dose group, and XJZ low dose group were given aspirin (300 mg/kg) by gavage in the morning and three different concentrations (12 g/kg, 6 g/kg, or 3 g/kg) of XJZ decoction by gavage in the afternoon; the mice in the positive control group were given aspirin (300 mg/kg) by gavage in the morning andomeprazole(20 mg/kg) by gavage in the afternoon. After the model was successfully constructed, the mice were anesthetized with isoflurane and gastric tissues were extracted for analysis. Click to Show/Hide
Response regulation	Xiaojianzhong (XJZ) significantly counteracted aspirin-induced gastric mucosal injury and inhibited oxidative stress and ferroptosis in mice. Upon examining SQSTM1/p62(p62)/ Kelch-like ECH-associated protein 1 (Keap1)/Nuclear Factor erythroid 2-Related Factor 2 (Nrf2), a well-known signaling pathway involved in the regulation of oxidative stress and ferroptosis, we found that its activation was significantly inhibited by aspirin treatment and that this signaling pathway was activated after XJZ intervention.

Auriculasin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[19]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell invasion
In Vitro Model	HCT 116 cells	Colon carcinoma	Homo sapiens	CVCL_0291
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
Response regulation	Auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1. AC can promote colorectal cancer cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and colony formation, indicating that AC has a significant tumor suppressor effect.

Calcitriol [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[21]
Drug for Ferroptosis	Suppressor
Response Target	Nuclear factor erythroid 2-related factor 2 (NFE2L2)		Suppressor; Marker	Target Info
Responsed Disease	Health		ICD-11: N.A.	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Pathways in cancer			hsa05200
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	ZFL cells	Normal	Danio rerio	CVCL_3276
Response regulation	This study confirmed the protective effect of calcitriol on RSL3-induced ferroptosis in zebrafish liver cells, and reported for the first time that calcitriol inhibits ferroptosis in fish cells by regulating the Keap1/Nrf2/GPx4 axis and NF-kB/hepcidin axis.

References

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Ref 2	Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib. Phytomedicine. 2023 Mar;111:154668. doi: 10.1016/j.phymed.2023.154668. Epub 2023 Jan 15.
Ref 3	Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis. Toxicol Mech Methods. 2023 Jan;33(1):47-55. doi: 10.1080/15376516.2022.2075297. Epub 2022 May 19.
Ref 4	Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3-Mediated Keap1/Nrf2/HO-1 Signalling Pathway. Front Genet. 2022 Mar 8;13:865073. doi: 10.3389/fgene.2022.865073. eCollection 2022.
Ref 5	Gastrodin Ameliorates Cognitive Dysfunction in Vascular Dementia Rats by Suppressing Ferroptosis via the Regulation of the Nrf2/Keap1-GPx4 Signaling Pathway. Molecules. 2022 Sep 24;27(19):6311. doi: 10.3390/molecules27196311.
Ref 6	Neurotrophic Role of the Next-Generation Probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson's Disease via Inhibiting Ferroptosis. Nutrients. 2022 Nov 18;14(22):4886. doi: 10.3390/nu14224886.
Ref 7	Astragaloside IV attenuates ferroptosis after subarachnoid hemorrhage via Nrf2/HO-1 signaling pathway. Front Pharmacol. 2022 Aug 19;13:924826. doi: 10.3389/fphar.2022.924826. eCollection 2022.
Ref 8	Astragaloside IV mitigates cerebral ischaemia-reperfusion injury via inhibition of P62/Keap1/Nrf2 pathway-mediated ferroptosis. Eur J Pharmacol. 2023 Apr 5;944:175516. doi: 10.1016/j.ejphar.2023.175516. Epub 2023 Feb 7.
Ref 9	Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis. J Nat Med. 2021 Jun;75(3):540-552. doi: 10.1007/s11418-021-01491-4. Epub 2021 Feb 15.
Ref 10	Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis. Free Radic Biol Med. 2023 Feb 20;196:108-120. doi: 10.1016/j.freeradbiomed.2023.01.006. Epub 2023 Jan 16.
Ref 11	Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis. J Ethnopharmacol. 2021 Jun 28;274:114064. doi: 10.1016/j.jep.2021.114064. Epub 2021 Mar 24.
Ref 12	Entacapone alleviates acute kidney injury by inhibiting ferroptosis. FASEB J. 2022 Jul;36(7):e22399. doi: 10.1096/fj.202200241RR.
Ref 13	Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling. Life Sci. 2023 Feb 15;315:121331. doi: 10.1016/j.lfs.2022.121331. Epub 2022 Dec 29.
Ref 14	Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury. Life Sci. 2022 Dec 15;311(Pt A):121091. doi: 10.1016/j.lfs.2022.121091. Epub 2022 Oct 14.
Ref 15	Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J Transl Med. 2021 Mar 2;19(1):96. doi: 10.1186/s12967-021-02745-1.
Ref 16	Exosomes Derived from Baicalin-Pretreated Mesenchymal Stem Cells Alleviate Hepatocyte Ferroptosis after Acute Liver Injury via the Keap1-NRF2 Pathway. Oxid Med Cell Longev. 2022 Jul 21;2022:8287227. doi: 10.1155/2022/8287227. eCollection 2022.
Ref 17	(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis. Cell Death Dis. 2020 Sep 19;11(9):781. doi: 10.1038/s41419-020-02961-5.
Ref 18	Xiaojianzhong decoction attenuates gastric mucosal injury by activating the p62/Keap1/Nrf2 signaling pathway to inhibit ferroptosis. Biomed Pharmacother. 2022 Nov;155:113631. doi: 10.1016/j.biopha.2022.113631. Epub 2022 Sep 16.
Ref 19	Auriculasin enhances ROS generation to regulate colorectal cancer cell apoptosis, ferroptosis, oxeiptosis, invasion and colony formation. Biochem Biophys Res Commun. 2022 Jan 8;587:99-106. doi: 10.1016/j.bbrc.2021.11.101. Epub 2021 Dec 1.
Ref 20	Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2. Cell Death Dis. 2022 Aug 29;13(8):742. doi: 10.1038/s41419-022-05192-y.
Ref 21	1,25(OH)(2)D(3) Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-B-hepcidin Axis. Int J Mol Sci. 2021 Oct 20;22(21):11334. doi: 10.3390/ijms222111334.

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Prof. Shuiping Liu