Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10112)

Regulator Name	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)
Synonyms	Activating transcription factor 4 Click to Show/Hide
Gene Name	ATF4
Gene ID	468
Regulator Type	Protein coding
Uniprot ID	P18848
Sequence	MTEMSFLSSEVLVGDLMSPFDQSGLGAEESLGLLDDYLEVAKHFKPHGFSSDKAKAGSSE WLAVDGLVSPSNNSKEDAFSGTDWMLEKMDLKEFDLDALLGIDDLETMPDDLLTTLDDTC DLFAPLVQETNKQPPQTVNPIGHLPESLTKPDQVAPFTFLQPLPLSPGVLSSTPDHSFSL ELGSEVDITEGDRKPDYTAYVAMIPQCIKEEDTPSDNDSGICMSPESYLGSPQHSPSTRG SPNRSLPSPGVLCGSARPKPYDPPGEKMVAAKVKGEKLDKKLKKMEQNKTAATRYRQKKR AEQEALTGECKELEKKNEALKERADSLAKEIQYLKDLIEEVRKARGKKRVP Click to Show/Hide
Family	BZIP family
Function	Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer. Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress. During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery. Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation. Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress. Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation. Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved. Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress. May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress. In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity. Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory. Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding. Click to Show/Hide
HGNC ID	HGNC:786
KEGG ID	hsa:468

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

ATF4 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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Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) [Driver; Marker]

Target Info

In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[1]
Target for Ferroptosis	Marker/Driver
Responsed Disease	Burkitt lymphoma		ICD-11: 2A85	Disease Info
Responsed Drug	Artesunate		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	Daudi cells	Burkitt lymphoma	Homo sapiens	CVCL_0008
	CA46 cells	Burkitt lymphoma	Homo sapiens	CVCL_1101
In Vivo Model	Four -week-old NOD/SCID mice were purchased from Chu Shang Technology (Kunming, China). CA-46 cells were collected and re-suspended in PBS at a concentration of 1-5 x 10⁷ cells/mL. Totally, 0.2 mL cells were inoculated subcutaneously in the middle and posterior armpits of mice. When the transplanted tumor was established, the mice were injected the artesunate solution intraperitoneally in accordance with the body weight (200 mg/kg) daily. Click to Show/Hide
Response regulation	Artesunate induced ferroptosis in different types of Burkitt's lymphoma cells, and caused a significant ERS response in tumor cells. The activation of the ATF4-CHOP-CHAC1 pathway up-regulated the expression of CHAC1 and degraded intracellular GSH, thus weakening the ability of lymphoma cells to resist ferroptosis.

Unspecific Target [Unspecific Target]

In total 5 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[2]
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Responsed Drug	RSL3		Investigative	Drug Info
Pathway Response	NF-kappa B signaling pathway			hsa04064
	Fatty acid metabolism			hsa01212
	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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 10⁶ U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm³, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks. Click to Show/Hide
Response regulation	NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.
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.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[4]
Responsed Disease	Injury of intra-abdominal organs		ICD-11: NB91	Disease Info
Responsed Drug	Microcystin-LR		Investigative	Drug Info
Pathway Response	Glutathione metabolism			hsa00480
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	hLCs (Liver cells)
In Vivo Model	In total, 90 common carp susceptible to MC-LR were obtained from Hulan Fishing Ground (Harbin, China) and acclimatized in 100 L glass aquaria (15 fish per tank) containing continuously aerated water at 23 under a 12 h light-dark cycle for 10 days prior to the experiments. Following acclimation, the fish in MC-LR treatment (M) group (45 fish in 3 tanks) were exposed to 10 ug/L of MC-LR for 15 days. The baseline mean body weights of the fish in the control (C) and M groups were 2.11 ± 0.03 and 2.12 ± 0.01 g, respectively. Click to Show/Hide
Response regulation	Microcystin-LR induces intestinal injury. Lesion morphological features (vacuolization, deformation and dilation of the endoplasmic reticulum [ER], absence of mitochondrial cristae in mid-intestine), up-regulated mRNA expressions of ER stress (eukaryotic translation initiation factor 2-alpha kinase 3, endoplasmic reticulum to nucleus signaling 1, activating transcription factor [ATF] 6, ATF4, DNA damage-inducible transcript 3), iron accumulation, and down-regulated activity of glutathione peroxidase (GPx) and glutathione (GSH) content were all typical characteristics of ferroptosis in intestinal tissue following MC-LR exposure.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[5]
Responsed Disease	Kidney injury		ICD-11: NB92	Disease Info
Responsed Drug	Cadmium		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TCMK-1 cells	Normal	Mus musculus	CVCL_2772
In Vivo Model	All specific pathogen free (SPF) grade Balb/c mice (6-8 weeks) were purchased from the Experimental Animal Center of Baiqiuem Medical College, Jilin University (China). The mice were reared under the conditions of 12 h of light and 12 h of darkness, supplemented with sufficient feed and free drinking water. The mice were treated according to a modified model as previous mentioned. In brief, a total of 15 mice were subjected to different doses of Cd (0, 2.5 and 5 mg/kg body weight/d) for 3 consecutive days intraperitoneally, and control mice were treated with 0.9% physiological saline. The concentrations of Cd were selected based on previous studies. At the day 4, the kidney tissue was collected and stored at -80 until detection. Click to Show/Hide
Response regulation	Cadmium activated the PERK-eIF2-ATF4-CHOP pathway and that inhibition of ER stress reduced ferroptosis caused by Cd. We further found that autophagy was required for Cd-induced ferroptosis because the inhibition of autophagy by chloroquine mitigated Cd-induced ferroptosis. Collectively, ferroptosis is involved in Cd-induced renal toxicity.
Experiment 5 Reporting the Ferroptosis Target of This Regulator				[8]
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	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
In Vivo Model	The 5-week-old nude mice (BALB/c) were purchased from Beijing HFK Bioscience Co., Ltd. (China). Hep3B cells (7 x 10⁶) stably transfected with NC1 or pre-miR-214 plasmid were subcutaneously injected into the nude mice. When the tumor sizes reached approximately >50 mm³, mice in Groups B and C were treated with 15 mg/kg erastin (MCE, China) twice every day for 20 days. Mice in Group A were treated with an equal volume vehicle. Click to Show/Hide
Response regulation	The ferroptosis-promoting effects of miR-214 in hepatocellular carcinoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]

Target Info

In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[6]
Target for Ferroptosis	Suppressor
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
In Vitro Model	BEL-7402 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_5492
Response regulation	The expression of ferroptosis-related protein GPX4 decreased after HULC knockdown, and the GPX4 expression level was reversed when the inhibitor miR-3200-5p was added simultaneously. HULC was found to function as a ceRNA of miR-3200-5p, and miR-3200-5p regulates ferroptosis by targeting ATF4, resulting in the inhibition of proliferation and metastasis within hepatocellular carcinoma cells.

Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]

Target Info

In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[7]
Target for Ferroptosis	Suppressor
Responsed Disease	Hepatocellular carcinoma		ICD-11: 2C12	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Hippo signaling pathway			hsa04390
Cell Process	Cell ferroptosis
In Vitro Model	HEK-293T cells	Normal	Homo sapiens	CVCL_0063
	SNU-398 cells	Adult hepatocellular carcinoma	Homo sapiens	CVCL_0077
	HT-1080 cells	Fibrosarcoma	Homo sapiens	CVCL_0317
	Huh-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0336
	HLE cells	Hepatocellular carcinoma	Homo sapiens	CVCL_1281
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	SNU398-parental cells, SNU398-shLuc, or SNU398-shYAP/TAZ cells (10⁶ in 100 ul PBS) were implanted into the left flanks of immunodeficient NOD/SCID; common receptor-/-(NSG) mice. When tumors were palpable, Sorafenib (LC Laboratories, S-8502) was applied at 20 mg/kg daily via gavage, SSA (Sulfasalazine, Sigma, S0883) was given at 120 mg/kg daily by intraperitoneal injection, 20 mM BSO (Lbuthionine-sulfoximine, Sigma, B2515) was given in the drinking water for 3 weeks. Click to Show/Hide
Response regulation	In a TEAD-dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling hepatocellular carcinoma cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression.

Burkitt lymphoma [ICD-11: 2A85]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator Info
Responsed Drug	Artesunate		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	Daudi cells	Burkitt lymphoma	Homo sapiens	CVCL_0008
	CA46 cells	Burkitt lymphoma	Homo sapiens	CVCL_1101
In Vivo Model	Four -week-old NOD/SCID mice were purchased from Chu Shang Technology (Kunming, China). CA-46 cells were collected and re-suspended in PBS at a concentration of 1-5 x 10⁷ cells/mL. Totally, 0.2 mL cells were inoculated subcutaneously in the middle and posterior armpits of mice. When the transplanted tumor was established, the mice were injected the artesunate solution intraperitoneally in accordance with the body weight (200 mg/kg) daily. Click to Show/Hide
Response regulation	Artesunate induced ferroptosis in different types of Burkitt's lymphoma cells, and caused a significant ERS response in tumor cells. The activation of the ATF4-CHOP-CHAC1 pathway up-regulated the expression of CHAC1 and degraded intracellular GSH, thus weakening the ability of lymphoma cells to resist ferroptosis.

Glioblastoma [ICD-11: 2A00]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator Info
Responsed Drug	RSL3		Investigative	Drug Info
Pathway Response	NF-kappa B signaling pathway			hsa04064
	Fatty acid metabolism			hsa01212
	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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 10⁶ U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm³, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks. Click to Show/Hide
Response regulation	NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.

Hepatocellular carcinoma [ICD-11: 2C12]

Disease Info

In total 3 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[6]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	SMMC-7721 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0534
In Vitro Model	BEL-7402 cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_5492
Response regulation	The expression of ferroptosis-related protein GPX4 decreased after HULC knockdown, and the GPX4 expression level was reversed when the inhibitor miR-3200-5p was added simultaneously. HULC was found to function as a ceRNA of miR-3200-5p, and miR-3200-5p regulates ferroptosis by targeting ATF4, resulting in the inhibition of proliferation and metastasis within hepatocellular carcinoma cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[7]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Hippo signaling pathway			hsa04390
Cell Process	Cell ferroptosis
In Vitro Model	HEK-293T cells	Normal	Homo sapiens	CVCL_0063
	SNU-398 cells	Adult hepatocellular carcinoma	Homo sapiens	CVCL_0077
	HT-1080 cells	Fibrosarcoma	Homo sapiens	CVCL_0317
	Huh-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0336
	HLE cells	Hepatocellular carcinoma	Homo sapiens	CVCL_1281
	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	SNU398-parental cells, SNU398-shLuc, or SNU398-shYAP/TAZ cells (10⁶ in 100 ul PBS) were implanted into the left flanks of immunodeficient NOD/SCID; common receptor-/-(NSG) mice. When tumors were palpable, Sorafenib (LC Laboratories, S-8502) was applied at 20 mg/kg daily via gavage, SSA (Sulfasalazine, Sigma, S0883) was given at 120 mg/kg daily by intraperitoneal injection, 20 mM BSO (Lbuthionine-sulfoximine, Sigma, B2515) was given in the drinking water for 3 weeks. Click to Show/Hide
Response regulation	In a TEAD-dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling hepatocellular carcinoma cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression.
Experiment 3 Reporting the Ferroptosis-centered Disease Response				[8]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator 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
In Vitro Model	Hep 3B2.1-7 cells	Hepatocellular carcinoma	Homo sapiens	CVCL_0326
In Vivo Model	The 5-week-old nude mice (BALB/c) were purchased from Beijing HFK Bioscience Co., Ltd. (China). Hep3B cells (7 x 10⁶) stably transfected with NC1 or pre-miR-214 plasmid were subcutaneously injected into the nude mice. When the tumor sizes reached approximately >50 mm³, mice in Groups B and C were treated with 15 mg/kg erastin (MCE, China) twice every day for 20 days. Mice in Group A were treated with an equal volume vehicle. Click to Show/Hide
Response regulation	The ferroptosis-promoting effects of miR-214 in hepatocellular carcinoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	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.

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			[4]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	Protein coding	Regulator Info
Responsed Drug	Microcystin-LR	Investigative	Drug Info
Pathway Response	Glutathione metabolism		hsa00480
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	hLCs (Liver cells)
In Vivo Model	In total, 90 common carp susceptible to MC-LR were obtained from Hulan Fishing Ground (Harbin, China) and acclimatized in 100 L glass aquaria (15 fish per tank) containing continuously aerated water at 23 under a 12 h light-dark cycle for 10 days prior to the experiments. Following acclimation, the fish in MC-LR treatment (M) group (45 fish in 3 tanks) were exposed to 10 ug/L of MC-LR for 15 days. The baseline mean body weights of the fish in the control (C) and M groups were 2.11 ± 0.03 and 2.12 ± 0.01 g, respectively. Click to Show/Hide
Response regulation	Microcystin-LR induces intestinal injury. Lesion morphological features (vacuolization, deformation and dilation of the endoplasmic reticulum [ER], absence of mitochondrial cristae in mid-intestine), up-regulated mRNA expressions of ER stress (eukaryotic translation initiation factor 2-alpha kinase 3, endoplasmic reticulum to nucleus signaling 1, activating transcription factor [ATF] 6, ATF4, DNA damage-inducible transcript 3), iron accumulation, and down-regulated activity of glutathione peroxidase (GPx) and glutathione (GSH) content were all typical characteristics of ferroptosis in intestinal tissue following MC-LR exposure.

Kidney injury [ICD-11: NB92]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[5]
Target Regulator	Cyclic AMP-dependent transcription factor ATF-4 (ATF4)		Protein coding	Regulator Info
Responsed Drug	Cadmium		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TCMK-1 cells	Normal	Mus musculus	CVCL_2772
In Vivo Model	All specific pathogen free (SPF) grade Balb/c mice (6-8 weeks) were purchased from the Experimental Animal Center of Baiqiuem Medical College, Jilin University (China). The mice were reared under the conditions of 12 h of light and 12 h of darkness, supplemented with sufficient feed and free drinking water. The mice were treated according to a modified model as previous mentioned. In brief, a total of 15 mice were subjected to different doses of Cd (0, 2.5 and 5 mg/kg body weight/d) for 3 consecutive days intraperitoneally, and control mice were treated with 0.9% physiological saline. The concentrations of Cd were selected based on previous studies. At the day 4, the kidney tissue was collected and stored at -80 until detection. Click to Show/Hide
Response regulation	Cadmium activated the PERK-eIF2-ATF4-CHOP pathway and that inhibition of ER stress reduced ferroptosis caused by Cd. We further found that autophagy was required for Cd-induced ferroptosis because the inhibition of autophagy by chloroquine mitigated Cd-induced ferroptosis. Collectively, ferroptosis is involved in Cd-induced renal toxicity.

Artesunate [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Inducer
Response Target	Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1)		Driver; Marker	Target Info
Responsed Disease	Burkitt lymphoma		ICD-11: 2A85	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	Daudi cells	Burkitt lymphoma	Homo sapiens	CVCL_0008
	CA46 cells	Burkitt lymphoma	Homo sapiens	CVCL_1101
In Vivo Model	Four -week-old NOD/SCID mice were purchased from Chu Shang Technology (Kunming, China). CA-46 cells were collected and re-suspended in PBS at a concentration of 1-5 x 10⁷ cells/mL. Totally, 0.2 mL cells were inoculated subcutaneously in the middle and posterior armpits of mice. When the transplanted tumor was established, the mice were injected the artesunate solution intraperitoneally in accordance with the body weight (200 mg/kg) daily. Click to Show/Hide
Response regulation	Artesunate induced ferroptosis in different types of Burkitt's lymphoma cells, and caused a significant ERS response in tumor cells. The activation of the ATF4-CHOP-CHAC1 pathway up-regulated the expression of CHAC1 and degraded intracellular GSH, thus weakening the ability of lymphoma cells to resist ferroptosis.

Cadmium [Investigative]

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	Unspecific Target
Responsed Disease	Kidney injury		ICD-11: NB92	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TCMK-1 cells	Normal	Mus musculus	CVCL_2772
In Vivo Model	All specific pathogen free (SPF) grade Balb/c mice (6-8 weeks) were purchased from the Experimental Animal Center of Baiqiuem Medical College, Jilin University (China). The mice were reared under the conditions of 12 h of light and 12 h of darkness, supplemented with sufficient feed and free drinking water. The mice were treated according to a modified model as previous mentioned. In brief, a total of 15 mice were subjected to different doses of Cd (0, 2.5 and 5 mg/kg body weight/d) for 3 consecutive days intraperitoneally, and control mice were treated with 0.9% physiological saline. The concentrations of Cd were selected based on previous studies. At the day 4, the kidney tissue was collected and stored at -80 until detection. Click to Show/Hide
Response regulation	Cadmium activated the PERK-eIF2-ATF4-CHOP pathway and that inhibition of ER stress reduced ferroptosis caused by Cd. We further found that autophagy was required for Cd-induced ferroptosis because the inhibition of autophagy by chloroquine mitigated Cd-induced ferroptosis. Collectively, ferroptosis is involved in Cd-induced renal toxicity.

RSL3 [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	Unspecific Target
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	NF-kappa B signaling pathway			hsa04064
	Fatty acid metabolism			hsa01212
	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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 10⁶ U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm³, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks. Click to Show/Hide
Response regulation	NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.

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.

Microcystin-LR [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[4]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Injury of intra-abdominal organs	ICD-11: NB91	Disease Info
Pathway Response	Glutathione metabolism		hsa00480
	Ferroptosis		hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	hLCs (Liver cells)
In Vivo Model	In total, 90 common carp susceptible to MC-LR were obtained from Hulan Fishing Ground (Harbin, China) and acclimatized in 100 L glass aquaria (15 fish per tank) containing continuously aerated water at 23 under a 12 h light-dark cycle for 10 days prior to the experiments. Following acclimation, the fish in MC-LR treatment (M) group (45 fish in 3 tanks) were exposed to 10 ug/L of MC-LR for 15 days. The baseline mean body weights of the fish in the control (C) and M groups were 2.11 ± 0.03 and 2.12 ± 0.01 g, respectively. Click to Show/Hide
Response regulation	Microcystin-LR induces intestinal injury. Lesion morphological features (vacuolization, deformation and dilation of the endoplasmic reticulum [ER], absence of mitochondrial cristae in mid-intestine), up-regulated mRNA expressions of ER stress (eukaryotic translation initiation factor 2-alpha kinase 3, endoplasmic reticulum to nucleus signaling 1, activating transcription factor [ATF] 6, ATF4, DNA damage-inducible transcript 3), iron accumulation, and down-regulated activity of glutathione peroxidase (GPx) and glutathione (GSH) content were all typical characteristics of ferroptosis in intestinal tissue following MC-LR exposure.

References

Ref 1	Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma. Biochem Biophys Res Commun. 2019 Nov 12;519(3):533-539. doi: 10.1016/j.bbrc.2019.09.023. Epub 2019 Sep 16.
Ref 2	RSL3 Drives Ferroptosis through NF-B Pathway Activation and GPX4 Depletion in Glioblastoma. Oxid Med Cell Longev. 2021 Dec 26;2021:2915019. doi: 10.1155/2021/2915019. eCollection 2021.
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	Microcystin-LR induces ferroptosis in intestine of common carp (Cyprinus carpio). Ecotoxicol Environ Saf. 2021 Oct 15;223:112610. doi: 10.1016/j.ecoenv.2021.112610. Epub 2021 Aug 5.
Ref 5	Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells. Free Radic Biol Med. 2021 Nov 1;175:236-248. doi: 10.1016/j.freeradbiomed.2021.09.008. Epub 2021 Sep 11.
Ref 6	Downregulation of HULC Induces Ferroptosis in Hepatocellular Carcinoma via Targeting of the miR-3200-5p/ATF4 Axis. Oxid Med Cell Longev. 2022 May 16;2022:9613095. doi: 10.1155/2022/9613095. eCollection 2022.
Ref 7	YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021 Dec 7;13(12):e14351. doi: 10.15252/emmm.202114351. Epub 2021 Oct 19.
Ref 8	MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol. 2020 Jul;235(7-8):5637-5648. doi: 10.1002/jcp.29496. Epub 2020 Jan 21.

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Prof. Shuiping Liu