Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10179)
Regulator Name Sestrin-2 (SESN2)
Synonyms
Hypoxia-induced gene
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Gene Name SESN2
Gene ID 83667
Regulator Type Protein coding
Uniprot ID P58004
Sequence
MIVADSECRAELKDYLRFAPGGVGDSGPGEEQRESRARRGPRGPSAFIPVEEVLREGAES
LEQHLGLEALMSSGRVDNLAVVMGLHPDYFTSFWRLHYLLLHTDGPLASSWRHYIAIMAA
ARHQCSYLVGSHMAEFLQTGGDPEWLLGLHRAPEKLRKLSEINKLLAHRPWLITKEHIQA
LLKTGEHTWSLAELIQALVLLTHCHSLSSFVFGCGILPEGDADGSPAPQAPTPPSEQSSP
PSRDPLNNSGGFESARDVEALMERMQQLQESLLRDEGTSQEEMESRFELEKSESLLVTPS
ADILEPSPHPDMLCFVEDPTFGYEDFTRRGAQAPPTFRAQDYTWEDHGYSLIQRLYPEGG
QLLDEKFQAAYSLTYNTIAMHSGVDTSVLRRAIWNYIHCVFGIRYDDYDYGEVNQLLERN
LKVYIKTVACYPEKTTRRMYNLFWRHFRHSEKVHVNLLLLEARMQAALLYALRAITRYMT

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Family Sestrin family
Function
Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway. This stress- inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1. May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1. May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein. Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed.

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HGNC ID
HGNC:20746
KEGG ID hsa:83667
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
SESN2 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 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Drug Empagliflozin Approved
 Drug Info 
Pathway Response Autophagy hsa04140
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
After a one-week acclimatization period, rats were randomly divided into four experimental groups of six rats each. Group I (the control group) received saline intraperitoneally in the same manner as BLM injections, as well as 1% carboxymethyl cellulose (CMC) orally in the same manner as EMPA. Group II (the BLM-treated group) received BLM (15 mg/kg) intraperitoneally three times per week for four successive weeks in order to induce pulmonary fibrosis. Group III (the EMPA-treated group) received EMPA dissolved in 1% CMC orally via oral gavage at a dose of 10 mg/kg/day throughout the experimental period. Group IV (the combined EMPA and BLM-treated group) received EMPA (10 mg/kg) orally via oral gavage seven days before BLM administration and continued for four weeks after BLM injection.

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Response regulation Empagliflozin has a promising protective effect against BLM-induced liver fibrosis in rats by enhancing autophagy and mitigating ferroptosis, inflammation, and ER stress via modulating the Sesn2/AMPK/Nrf2/HO-1 signaling pathway.
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Responsed Disease Injury of intra-abdominal organs ICD-11: NB91
 Disease Info 
Responsed Drug Erastin 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
AML12 cells Normal Mus musculus CVCL_0140
mEFs (Mouse embryonic fibroblasts)
In Vivo Model
Six-weeks-old male ICR mice were obtained from Orient Bio (Sungnam, Korea) and acclimatized for 1 week. For Sesn2 overexpression, ICR mice were injected with the recombinant adenovirus particles (1 x 109 pfu) suspended in phosphate-buffered saline with tail vein. After 48 h, phenylhydrazine (PHZ, 60 mg/kg, i.p.) was administered to induce iron accumulation and liver injury.

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Response regulation Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Collectively, ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.
Liver fibrosis [ICD-11: DB93]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Sestrin-2 (SESN2) Protein coding
 Regulator Info 
Responsed Drug Empagliflozin Approved
 Drug Info 
Pathway Response Autophagy hsa04140
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
After a one-week acclimatization period, rats were randomly divided into four experimental groups of six rats each. Group I (the control group) received saline intraperitoneally in the same manner as BLM injections, as well as 1% carboxymethyl cellulose (CMC) orally in the same manner as EMPA. Group II (the BLM-treated group) received BLM (15 mg/kg) intraperitoneally three times per week for four successive weeks in order to induce pulmonary fibrosis. Group III (the EMPA-treated group) received EMPA dissolved in 1% CMC orally via oral gavage at a dose of 10 mg/kg/day throughout the experimental period. Group IV (the combined EMPA and BLM-treated group) received EMPA (10 mg/kg) orally via oral gavage seven days before BLM administration and continued for four weeks after BLM injection.

    Click to Show/Hide
Response regulation Empagliflozin has a promising protective effect against BLM-induced liver fibrosis in rats by enhancing autophagy and mitigating ferroptosis, inflammation, and ER stress via modulating the Sesn2/AMPK/Nrf2/HO-1 signaling pathway.
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 [2]
Target Regulator Sestrin-2 (SESN2) Protein coding
 Regulator Info 
Responsed Drug Erastin 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
AML12 cells Normal Mus musculus CVCL_0140
mEFs (Mouse embryonic fibroblasts)
In Vivo Model
Six-weeks-old male ICR mice were obtained from Orient Bio (Sungnam, Korea) and acclimatized for 1 week. For Sesn2 overexpression, ICR mice were injected with the recombinant adenovirus particles (1 x 109 pfu) suspended in phosphate-buffered saline with tail vein. After 48 h, phenylhydrazine (PHZ, 60 mg/kg, i.p.) was administered to induce iron accumulation and liver injury.

    Click to Show/Hide
Response regulation Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Collectively, ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.
Empagliflozin [Approved]
 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 Liver fibrosis ICD-11: DB93
 Disease Info 
Pathway Response Autophagy hsa04140
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
After a one-week acclimatization period, rats were randomly divided into four experimental groups of six rats each. Group I (the control group) received saline intraperitoneally in the same manner as BLM injections, as well as 1% carboxymethyl cellulose (CMC) orally in the same manner as EMPA. Group II (the BLM-treated group) received BLM (15 mg/kg) intraperitoneally three times per week for four successive weeks in order to induce pulmonary fibrosis. Group III (the EMPA-treated group) received EMPA dissolved in 1% CMC orally via oral gavage at a dose of 10 mg/kg/day throughout the experimental period. Group IV (the combined EMPA and BLM-treated group) received EMPA (10 mg/kg) orally via oral gavage seven days before BLM administration and continued for four weeks after BLM injection.

    Click to Show/Hide
Response regulation Empagliflozin has a promising protective effect against BLM-induced liver fibrosis in rats by enhancing autophagy and mitigating ferroptosis, inflammation, and ER stress via modulating the Sesn2/AMPK/Nrf2/HO-1 signaling pathway.
Erastin [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 Injury of intra-abdominal organs ICD-11: NB91
 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
AML12 cells Normal Mus musculus CVCL_0140
mEFs (Mouse embryonic fibroblasts)
In Vivo Model
Six-weeks-old male ICR mice were obtained from Orient Bio (Sungnam, Korea) and acclimatized for 1 week. For Sesn2 overexpression, ICR mice were injected with the recombinant adenovirus particles (1 x 109 pfu) suspended in phosphate-buffered saline with tail vein. After 48 h, phenylhydrazine (PHZ, 60 mg/kg, i.p.) was administered to induce iron accumulation and liver injury.

    Click to Show/Hide
Response regulation Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Collectively, ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.
References
Ref 1 Empagliflozin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Modulating Sesn2/AMPK/Nrf2 Signaling and Targeting Ferroptosis and Autophagy. Int J Mol Sci. 2023 May 30;24(11):9481. doi: 10.3390/ijms24119481.
Ref 2 Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019 Sep 15;379:114665. doi: 10.1016/j.taap.2019.114665. Epub 2019 Jul 16.