Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10209)

Regulator Name	Sequestosome-1 (SQSTM1)
Synonyms	ORCA, OSIL; EBI3-associated protein of 60 kDa; Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa; Ubiquitin-binding protein p62 Click to Show/Hide
Gene Name	SQSTM1
Gene ID	8878
Regulator Type	Protein coding
Uniprot ID	Q13501
Sequence	MASLTVKAYLLGKEDAAREIRRFSFCCSPEPEAEAEAAAGPGPCERLLSRVAALFPALRP GGFQAHYRDEDGDLVAFSSDEELTMAMSYVKDDIFRIYIKEKKECRRDHRPPCAQEAPRN MVHPNVICDGCNGPVVGTRYKCSVCPDYDLCSVCEGKGLHRGHTKLAFPSPFGHLSEGFS HSRWLRKVKHGHFGWPGWEMGPPGNWSPRPPRAGEARPGPTAESASGPSEDPSVNFLKNV GESVAAALSPLGIEVDIDVEHGGKRSRLTPVSPESSSTEEKSSSQPSSCCSDPSKPGGNV EGATQSLAEQMRKIALESEGRPEEQMESDNCSGGDDDWTHLSSKEVDPSTGELQSLQMPE SEGPSSLDPSQEGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGWLTRLLQTK NYDIGAALDTIQYSKHPPPL Click to Show/Hide
Function	Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family. Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus. Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes. Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes. Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation. Click to Show/Hide
HGNC ID	HGNC:11280
KEGG ID	hsa:8878

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

SQSTM1 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).

Browse Target

Browse Disease

Browse Drug

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

Target Info

In total 5 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[1]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Responsed Drug	Sorafenib		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hepa 1-6 cells	Hepatocellular carcinoma	Mus musculus	CVCL_0327
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	To generate murine subcutaneous tumors, 1 x 10⁶ Hepa16 cells in control shRNA or NRF2 knockdown cells in 200 ul phosphate buffered saline were injected subcutaneously to the right of the dorsal midline in C57BL/6 mice. Once the tumors reached 80-100 mm³ at day seven, mice were randomly allocated into groups and treated with erastin (30 mg/kg intraperitoneal injection [i.p.], twice every other day) and sorafenib (10 mg/kg i.p., once every other day) for two weeks. Click to Show/Hide
Response regulation	Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 (SQSTM1) expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. The status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in hepatocellular carcinoma cells.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[2]
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 3 Reporting the Ferroptosis Target of This Regulator				[3]
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 4 Reporting the Ferroptosis Target of This Regulator				[4]
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 5 Reporting the Ferroptosis Target of This Regulator				[5]
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).

Hepatocellular carcinoma [ICD-11: 2C12]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Sequestosome-1 (SQSTM1)		Protein coding	Regulator Info
Responsed Drug	Sorafenib		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hepa 1-6 cells	Hepatocellular carcinoma	Mus musculus	CVCL_0327
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	To generate murine subcutaneous tumors, 1 x 10⁶ Hepa16 cells in control shRNA or NRF2 knockdown cells in 200 ul phosphate buffered saline were injected subcutaneously to the right of the dorsal midline in C57BL/6 mice. Once the tumors reached 80-100 mm³ at day seven, mice were randomly allocated into groups and treated with erastin (30 mg/kg intraperitoneal injection [i.p.], twice every other day) and sorafenib (10 mg/kg i.p., once every other day) for two weeks. Click to Show/Hide
Response regulation	Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 (SQSTM1) expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. The status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in hepatocellular carcinoma cells.

Cerebral ischemia [ICD-11: 8B10]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Sequestosome-1 (SQSTM1)		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.

Endometrial hyperplasia [ICD-11: GA16]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[3]
Target Regulator	Sequestosome-1 (SQSTM1)	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				[4]
Target Regulator	Sequestosome-1 (SQSTM1)		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).

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

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[5]
Target Regulator	Sequestosome-1 (SQSTM1)	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).

Entacapone [Approved]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[4]
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 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[2]
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.

Baicalin [Terminated]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[5]
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).

Guizhi Fuling Capsule [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	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.

Sorafenib [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Suppressor
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	Fatty acid metabolism			hsa01212
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	Hep-G2 cells	Hepatoblastoma	Homo sapiens	CVCL_0027
	Hepa 1-6 cells	Hepatocellular carcinoma	Mus musculus	CVCL_0327
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	To generate murine subcutaneous tumors, 1 x 10⁶ Hepa16 cells in control shRNA or NRF2 knockdown cells in 200 ul phosphate buffered saline were injected subcutaneously to the right of the dorsal midline in C57BL/6 mice. Once the tumors reached 80-100 mm³ at day seven, mice were randomly allocated into groups and treated with erastin (30 mg/kg intraperitoneal injection [i.p.], twice every other day) and sorafenib (10 mg/kg i.p., once every other day) for two weeks. Click to Show/Hide
Response regulation	Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 (SQSTM1) expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. The status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in hepatocellular carcinoma cells.

References

Ref 1	Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016 Jan;63(1):173-84. doi: 10.1002/hep.28251. Epub 2015 Nov 26.
Ref 2	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 3	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 4	Entacapone alleviates acute kidney injury by inhibiting ferroptosis. FASEB J. 2022 Jul;36(7):e22399. doi: 10.1096/fj.202200241RR.
Ref 5	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.

Ferroptosis Regulator Information

About FERREG

Visitor Map

Correspondence

Prof. Shuiping Liu