Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10090)

Regulator Name	Endoplasmic reticulum chaperone BiP (HSPA5)
Synonyms	78 kDa glucose-regulated protein Click to Show/Hide
Gene Name	HSPA5
Gene ID	3309
Regulator Type	Protein coding
Uniprot ID	P11021
Sequence	MKLSLVAAMLLLLSAARAEEEDKKEDVGTVVGIDLGTTYSCVGVFKNGRVEIIANDQGNR ITPSYVAFTPEGERLIGDAAKNQLTSNPENTVFDAKRLIGRTWNDPSVQQDIKFLPFKVV EKKTKPYIQVDIGGGQTKTFAPEEISAMVLTKMKETAEAYLGKKVTHAVVTVPAYFNDAQ RQATKDAGTIAGLNVMRIINEPTAAAIAYGLDKREGEKNILVFDLGGGTFDVSLLTIDNG VFEVVATNGDTHLGGEDFDQRVMEHFIKLYKKKTGKDVRKDNRAVQKLRREVEKAKRALS SQHQARIEIESFYEGEDFSETLTRAKFEELNMDLFRSTMKPVQKVLEDSDLKKSDIDEIV LVGGSTRIPKIQQLVKEFFNGKEPSRGINPDEAVAYGAAVQAGVLSGDQDTGDLVLLDVC PLTLGIETVGGVMTKLIPRNTVVPTKKSQIFSTASDNQPTVTIKVYEGERPLTKDNHLLG TFDLTGIPPAPRGVPQIEVTFEIDVNGILRVTAEDKGTGNKNKITITNDQNRLTPEEIER MVNDAEKFAEEDKKLKERIDTRNELESYAYSLKNQIGDKEKLGGKLSSEDKETMEKAVEE KIEWLESHQDADIEDFKAKKKELEEIVQPIISKLYGSAGPPPTGEEDTAEKDEL Click to Show/Hide
Family	Heat shock protein 70 family
Function	Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen. Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate. Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1. Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1. Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation. Click to Show/Hide
HGNC ID	HGNC:5238
KEGG ID	hsa:3309

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

HSPA5 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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Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]

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	Glioblastoma		ICD-11: 2A00	Disease Info
Responsed Drug	Dihydroartemisinin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.
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	Dihydroartemisinin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[4]
Target for Ferroptosis	Suppressor
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	DLD-1 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0248
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
In Vivo Model	Male BALB/c nude mice (4-6 weeks) were purchased from the Air Force Medical University Laboratory Animal Center. The mice were kept in the SPF environment and had free access to food and water. 3 x 10⁶ SW480 cells were injected subcutaneously into nude mice (n = 4 or 5). Erastin was dissolved in 5% DMSO/corn oil and intraperitoneally injected into nude mice at a dose of 15 mg/kg three times. Three weeks later, mice were anesthetized by intraperitoneal injection of 10% chloral hydrate (35 mg/kg). When mice were successfully anesthetized five minutes later, mice were sacrificed and the tumors were resected and weighed. The tumors were divided into two parts. One sample was lysed and used for protein analysis. The other part was used to test for Ki67 expression. Click to Show/Hide
Response regulation	HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. HSPA5 was demonstrated to play a diagnostic role and correlated to the immune microenvironment in CRC patients.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[5]
Target for Ferroptosis	Marker/Suppressor
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
	CFPAC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_1119
	MIA PaCa-2 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0428
	Panc 02.03 cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1633
	Panc02 cells	Pancreatic ductal adenocarcinoma	Mus musculus	CVCL_D627
In Vivo Model	To generate murine subcutaneous tumors, 2 x 10⁶ PANC1 cells were injected subcutaneously to the right of the dorsal midline in nude mice. Once the tumors reached ~50 mm³ at day seven, mice were randomly allocated into groups and treated with chemotherapy for two weeks (n = 5 mice/group). To generate orthotopic tumors, B6 mice were surgically implanted with 1 x 10⁶ Panc02 into the tail of the pancreas. Two weeks after implantation, mice were randomly allocated into groups and treated with chemotherapy for three weeks (n = 6 mice/group). Click to Show/Hide
Response regulation	The HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosisin vitroand in both subcutaneous and orthotopic animal models of pancreatic ductal adenocarcinoma.
Experiment 5 Reporting the Ferroptosis Target of This Regulator				[6]
Target for Ferroptosis	Suppressor
Responsed Disease	Degenerative arthritis		ICD-11: FA05	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	A rat model of OA with destabilization of the medial meniscus was established . After anesthetization with 3% pentobarbital sodium (Tocris, Avonmouth, UK), the hair on the right knee was clipped. Right knee was subsequently exposed before an incision was made in the medial aspect of the joint capsule, then the anterior cruciate ligament was transected, and the medial meniscus was completely resected in a manner that did not injure the articular cartilage. Subsequently, the joint was irrigated with normal saline, the capsule was sutured with 4-0 chromic catgut, and the skin was closed with 4-0 nylon mattress sutures. And the rats were allowed to move, eat, and drink freely after surgery. Experimental groups are as follows: sham group (A medial incision was made to expose the knee joint cavity, and sutured), OA model group (Destabilization of the medial meniscus), sh-NC group (OA rats were injected with sh-NC), and sh-SND1 group (OA rats were injected with sh-SND1). Click to Show/Hide
Response regulation	The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

Unspecific Target [Unspecific Target]

In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[2]
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Responsed Drug	Artesunate		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	PaTu 8988t cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1847
	AsPC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0152
In Vivo Model	AsPC-1 cells (1 x 10⁶) with a control or GRP78 shRNA transfection were injected into right subcutaneous flank of nude mice (five mice per group). The nude mice were randomized into two groups and treated with DMSO or artesunate (30 mg/kg/i.p.), respectively. Artesunate was administered every two days. The tumor growth speed and volume were monitored every two days until the end point at day 35. All the tumor size and weight in the artesunate-treated groups were measured by using a caliper and an electronic balance. Click to Show/Hide
Response regulation	Artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 (HSPA5) enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[3]
Responsed Disease	Traumatic brain injury		ICD-11: NA07	Disease Info
Responsed Drug	Baicalein		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	rRHs (Rat right hemispheres)
In Vivo Model	Healthy male Sprague-Dawley rats (weighing 370 g-420 g) were purchased from the Laboratory Animal Center of Sun Yat-sen University. The rats were randomized into five groups. Rats in sham group (n = 6) underwent the same anesthetic and surgical procedures, excluding cardiac arrest and CPR. All of the remaining four groups were given the interventions within 10 minutes of ROSC. Rats in CPR group (n = 6) received an intraperitoneal injection of 0.9% saline (1 mL/kg). Rats in baicalein group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein at the same time, based on previous studies. Rats in tunicamycin group (n = 6) were intraperitoneally injected with tunicamycin (2 mg/kg body weight) (22-24). Rats in baicalein + tunicamycin group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein and 2 mg/kg (body weight) tunicamycin. All groups were given the same volume of normal saline solvent (2 mL/kg). Click to Show/Hide
Response regulation	Our research suggests that baicalein inhibited ferroptosis after ROSC by targeting ALOX15. Iron content, and MDA were reduced. More importantly, baicalein alleviated ER stress by inhibiting the expression of GRP78, ATF4, and CHOP. Baicalein is a potential drug to relieve brain injury after ROSC.

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	Endoplasmic reticulum chaperone BiP (HSPA5)		Protein coding	Regulator Info
Responsed Drug	Dihydroartemisinin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)		Protein coding	Regulator Info
Responsed Drug	Dihydroartemisinin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.

Colorectal cancer [ICD-11: 2B91]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[4]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)		Protein coding	Regulator Info
Pathway Response	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	DLD-1 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0248
	SW480 cells	Colon adenocarcinoma	Homo sapiens	CVCL_0546
In Vivo Model	Male BALB/c nude mice (4-6 weeks) were purchased from the Air Force Medical University Laboratory Animal Center. The mice were kept in the SPF environment and had free access to food and water. 3 x 10⁶ SW480 cells were injected subcutaneously into nude mice (n = 4 or 5). Erastin was dissolved in 5% DMSO/corn oil and intraperitoneally injected into nude mice at a dose of 15 mg/kg three times. Three weeks later, mice were anesthetized by intraperitoneal injection of 10% chloral hydrate (35 mg/kg). When mice were successfully anesthetized five minutes later, mice were sacrificed and the tumors were resected and weighed. The tumors were divided into two parts. One sample was lysed and used for protein analysis. The other part was used to test for Ki67 expression. Click to Show/Hide
Response regulation	HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. HSPA5 was demonstrated to play a diagnostic role and correlated to the immune microenvironment in CRC patients.

Pancreatic cancer [ICD-11: 2C10]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)		Protein coding	Regulator Info
Responsed Drug	Artesunate		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	PaTu 8988t cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1847
In Vitro Model	AsPC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0152
In Vivo Model	AsPC-1 cells (1 x 10⁶) with a control or GRP78 shRNA transfection were injected into right subcutaneous flank of nude mice (five mice per group). The nude mice were randomized into two groups and treated with DMSO or artesunate (30 mg/kg/i.p.), respectively. Artesunate was administered every two days. The tumor growth speed and volume were monitored every two days until the end point at day 35. All the tumor size and weight in the artesunate-treated groups were measured by using a caliper and an electronic balance. Click to Show/Hide
Response regulation	Artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 (HSPA5) enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[5]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)		Protein coding	Regulator Info
Pathway Response	Fatty acid metabolism			hsa01212
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
	CFPAC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_1119
	MIA PaCa-2 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0428
	Panc 02.03 cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1633
	Panc02 cells	Pancreatic ductal adenocarcinoma	Mus musculus	CVCL_D627
In Vivo Model	To generate murine subcutaneous tumors, 2 x 10⁶ PANC1 cells were injected subcutaneously to the right of the dorsal midline in nude mice. Once the tumors reached ~50 mm³ at day seven, mice were randomly allocated into groups and treated with chemotherapy for two weeks (n = 5 mice/group). To generate orthotopic tumors, B6 mice were surgically implanted with 1 x 10⁶ Panc02 into the tail of the pancreas. Two weeks after implantation, mice were randomly allocated into groups and treated with chemotherapy for three weeks (n = 6 mice/group). Click to Show/Hide
Response regulation	The HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosisin vitroand in both subcutaneous and orthotopic animal models of pancreatic ductal adenocarcinoma.

Degenerative arthritis [ICD-11: FA05]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[6]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)	Protein coding	Regulator Info
Pathway Response	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	hCDs (Chondrocytes)
In Vivo Model	A rat model of OA with destabilization of the medial meniscus was established . After anesthetization with 3% pentobarbital sodium (Tocris, Avonmouth, UK), the hair on the right knee was clipped. Right knee was subsequently exposed before an incision was made in the medial aspect of the joint capsule, then the anterior cruciate ligament was transected, and the medial meniscus was completely resected in a manner that did not injure the articular cartilage. Subsequently, the joint was irrigated with normal saline, the capsule was sutured with 4-0 chromic catgut, and the skin was closed with 4-0 nylon mattress sutures. And the rats were allowed to move, eat, and drink freely after surgery. Experimental groups are as follows: sham group (A medial incision was made to expose the knee joint cavity, and sutured), OA model group (Destabilization of the medial meniscus), sh-NC group (OA rats were injected with sh-NC), and sh-SND1 group (OA rats were injected with sh-SND1). Click to Show/Hide
Response regulation	The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

Traumatic brain injury [ICD-11: NA07]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[3]
Target Regulator	Endoplasmic reticulum chaperone BiP (HSPA5)	Protein coding	Regulator Info
Responsed Drug	Baicalein	Investigative	Drug Info
Pathway Response	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	rRHs (Rat right hemispheres)
In Vivo Model	Healthy male Sprague-Dawley rats (weighing 370 g-420 g) were purchased from the Laboratory Animal Center of Sun Yat-sen University. The rats were randomized into five groups. Rats in sham group (n = 6) underwent the same anesthetic and surgical procedures, excluding cardiac arrest and CPR. All of the remaining four groups were given the interventions within 10 minutes of ROSC. Rats in CPR group (n = 6) received an intraperitoneal injection of 0.9% saline (1 mL/kg). Rats in baicalein group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein at the same time, based on previous studies. Rats in tunicamycin group (n = 6) were intraperitoneally injected with tunicamycin (2 mg/kg body weight) (22-24). Rats in baicalein + tunicamycin group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein and 2 mg/kg (body weight) tunicamycin. All groups were given the same volume of normal saline solvent (2 mL/kg). Click to Show/Hide
Response regulation	Our research suggests that baicalein inhibited ferroptosis after ROSC by targeting ALOX15. Iron content, and MDA were reduced. More importantly, baicalein alleviated ER stress by inhibiting the expression of GRP78, ATF4, and CHOP. Baicalein is a potential drug to relieve brain injury after ROSC.

Dihydroartemisinin [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Suppressor
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Suppressor
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
	U-373MG cells	Astrocytoma	Homo sapiens	CVCL_2219
	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Specific pathogen-free athymic nude BALB/c mice (4-6 weeks old) were obtained from Guangdong Experimental Animal Centre (Guangzhou, China). To generate murine subcutaneous tumors, cells (for U251: 2 x 10⁶ cells; for U373: 2 x 10⁶ cells) were suspended in 0.2 ml PBS and injected into the flanks of mice (n = 6/group). Tumor volume was measured once every 3 days using calipers. Click to Show/Hide
Response regulation	HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized Dihydroartemisinin-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis.

Artesunate [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	Unspecific Target
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	PaTu 8988t cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1847
	AsPC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0152
In Vivo Model	AsPC-1 cells (1 x 10⁶) with a control or GRP78 shRNA transfection were injected into right subcutaneous flank of nude mice (five mice per group). The nude mice were randomized into two groups and treated with DMSO or artesunate (30 mg/kg/i.p.), respectively. Artesunate was administered every two days. The tumor growth speed and volume were monitored every two days until the end point at day 35. All the tumor size and weight in the artesunate-treated groups were measured by using a caliper and an electronic balance. Click to Show/Hide
Response regulation	Artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 (HSPA5) enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.

Baicalein [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[3]
Drug for Ferroptosis	Suppressor
Response Target	Unspecific Target
Responsed Disease	Traumatic brain injury	ICD-11: NA07	Disease Info
Pathway Response	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	rRHs (Rat right hemispheres)
In Vivo Model	Healthy male Sprague-Dawley rats (weighing 370 g-420 g) were purchased from the Laboratory Animal Center of Sun Yat-sen University. The rats were randomized into five groups. Rats in sham group (n = 6) underwent the same anesthetic and surgical procedures, excluding cardiac arrest and CPR. All of the remaining four groups were given the interventions within 10 minutes of ROSC. Rats in CPR group (n = 6) received an intraperitoneal injection of 0.9% saline (1 mL/kg). Rats in baicalein group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein at the same time, based on previous studies. Rats in tunicamycin group (n = 6) were intraperitoneally injected with tunicamycin (2 mg/kg body weight) (22-24). Rats in baicalein + tunicamycin group (n = 6) were intraperitoneally injected with 50 mg/kg (body weight) baicalein and 2 mg/kg (body weight) tunicamycin. All groups were given the same volume of normal saline solvent (2 mL/kg). Click to Show/Hide
Response regulation	Our research suggests that baicalein inhibited ferroptosis after ROSC by targeting ALOX15. Iron content, and MDA were reduced. More importantly, baicalein alleviated ER stress by inhibiting the expression of GRP78, ATF4, and CHOP. Baicalein is a potential drug to relieve brain injury after ROSC.

References

Ref 1	Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells. J Exp Clin Cancer Res. 2019 Sep 13;38(1):402. doi: 10.1186/s13046-019-1413-7.
Ref 2	Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Des Devel Ther. 2019 Jul 2;13:2135-2144. doi: 10.2147/DDDT.S199459. eCollection 2019.
Ref 3	BAICALEIN RELIEVES BRAIN INJURY VIA INHIBITING FERROPTOSIS AND ENDOPLASMIC RETICULUM STRESS IN A RAT MODEL OF CARDIAC ARREST. Shock. 2023 Mar 1;59(3):434-441. doi: 10.1097/SHK.0000000000002058. Epub 2022 Nov 26.
Ref 4	HSPA5 repressed ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Neoplasma. 2022 Sep;69(5):1054-1069. doi: 10.4149/neo_2022_220331N363. Epub 2022 Jun 20.
Ref 5	HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res. 2017 Apr 15;77(8):2064-2077. doi: 10.1158/0008-5472.CAN-16-1979. Epub 2017 Jan 27.
Ref 6	The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes. Inflamm Res. 2022 Apr;71(4):461-472. doi: 10.1007/s00011-022-01547-5. Epub 2022 Mar 23.

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Correspondence

Prof. Shuiping Liu