Affinage

SESN2

Sestrin-2 · UniProt P58004

Length
480 aa
Mass
54.5 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SESN2 is a stress-inducible cytoprotective protein that integrates signals from hypoxia, DNA damage, oxidative stress, ER stress, and nutrient deprivation to restrain mTORC1 signaling and promote autophagy/mitophagy (PMID:12203114, PMID:28783174, PMID:34429398). Its principal anabolic-restraining function is inhibition of mTORC1: SESN2 binds the GATOR2 complex, relieving GATOR2 suppression of GATOR1, which stimulates RagA/B GTPase activity and prevents lysosomal recruitment/activation of mTORC1 in amino-acid- and stress-sensing contexts (PMID:32287270, PMID:29500367). Independently of mTORC1, SESN2 drives selective clearance of damaged mitochondria: triggered by mitochondrial superoxide, it interacts with ULK1 to elevate ULK1 levels and promote ULK1-mediated phosphorylation of Beclin1 at Ser14, enabling cytosolic Parkin–Beclin1/SQSTM1 assembly and PINK1-dependent translocation of Parkin and SQSTM1 to damaged mitochondria via two distinct functional domains (PMID:29330382, PMID:36632468, PMID:27337507, PMID:31199952). Through these activities SESN2 suppresses prolonged NLRP3 inflammasome activation and protects against tissue injury in sepsis, cardiomyopathy, and disc degeneration (PMID:27337507, PMID:31199952, PMID:36632468). SESN2 also acts upstream of the NRF2 antioxidant program—enhancing NRF2 via p62-dependent autophagy and AKT1-Ser473 phosphorylation—and limits ferroptosis and ROS (PMID:27463837, PMID:33231566, PMID:34923100, PMID:42105713). Beyond redox and autophagy control, SESN2 restrains lipogenesis by binding SCAP to block SREBP1 activation (PMID:40822351), suppresses STAT3 by maintaining the phosphatase PTPRD (PMID:39985075), and regulates AMPK activation by promoting AMPK–LKB1 complex formation (PMID:36994173). SESN2 expression is tightly controlled: it is transcriptionally induced by p53, ATF4/CHOP, C/EBPβ, and JUN (PMID:12203114, PMID:29599707, PMID:31337142, PMID:34429398, PMID:27171279); epigenetically repressed by LSD1, JMJD3, and SETDB1/HP1β at its promoter (PMID:28783174, PMID:33117796, PMID:39443993); post-transcriptionally regulated by miR-182-5p and FTO/IGF2BP1-dependent m6A control (PMID:29662624, PMID:38495179); and stabilized or degraded through K48-linked ubiquitination by RBX1 versus deubiquitination by OTUB1, the latter exploited by KSHV vCyclin to sustain AMPK-driven lymphoma survival (PMID:29294217, PMID:41196342).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established SESN2 as a stress-responsive gene, defining the inducing signals (hypoxia, p53-dependent DNA damage, p53-independent oxidative stress) and its context-dependent role in cell death versus protection.

    Evidence cDNA microarray and conditional (tet-off) overexpression with viability assays

    PMID:12203114

    Open questions at the time
    • No molecular partner or pathway mechanism identified
    • Pro-death versus pro-survival switch unexplained
  2. 2016 High

    Defined SESN2 as a driver of mitophagy that limits inflammation, linking it mechanistically to SQSTM1-mediated mitochondrial priming and ULK1 upregulation in vivo.

    Evidence Sesn2-knockout mice in two sepsis models, Co-IP, ubiquitin-binding assays, and imaging in macrophages

    PMID:27337507

    Open questions at the time
    • Domain mediating SQSTM1/ubiquitin engagement not mapped
    • Mechanism of ULK1 protein-level increase unresolved
  3. 2016 Medium

    Identified the JNK/JUN-AP1 axis and the p53/AKT3 and mitochondrial routes as distinct upstream inducers of SESN2, expanding the transcriptional input map and placing SESN2 upstream of Nrf2.

    Evidence ChIP/AP-1 reporter, kinase inhibitors, siRNA, ROS and DNA-damage assays across stimuli

    PMID:27171279 PMID:27463837

    Open questions at the time
    • How SESN2 negatively regulates DNA-damage repair is unclear
    • Molecular link from SESN2 to Nrf2 not yet defined
  4. 2017 High

    Placed SESN2 within an epigenetic repression circuit, showing LSD1 (H3K4me2) at the promoter restrains SESN2-driven mTORC1 inhibition and autophagy.

    Evidence ChIP, LSD1 inhibitors/knockdown, mTORC1 and autophagy readouts in neuroblastoma

    PMID:28783174

    Open questions at the time
    • Cofactors recruiting LSD1 to the SESN2 promoter unidentified
  5. 2018 High

    Resolved the molecular mechanism of SESN2-driven mitophagy: ULK1 interaction and Beclin1-S14 phosphorylation gate cytosolic Parkin assembly (PINK1-independent) prior to PINK1-dependent mitochondrial translocation.

    Evidence Reciprocal Co-IP, phosphosite mapping, superoxide scavenging, PINK1 epistasis

    PMID:29330382

    Open questions at the time
    • Direct kinase/substrate biochemistry of the SESN2-ULK1-Beclin1 step not reconstituted
  6. 2018 Medium

    Defined post-translational and additional transcriptional control of SESN2, identifying RBX1 as a K48-linked E3 ligase driving SESN2 degradation, ATF4 as a BDNF/TrkB-driven inducer, and amino-acid-sensitive mTORC1 suppression.

    Evidence Co-IP/ubiquitination assays, transcriptome and ATF4 knockdown, gain/loss-of-function mTORC1 readouts

    PMID:29294217 PMID:29500367 PMID:29599707

    Open questions at the time
    • RBX1 partner cullin/adaptor not defined
    • Degron on SESN2 not mapped
  7. 2019 High

    Confirmed the SESN2-Parkin-SQSTM1 mitophagy module in cardiac tissue and extended it to CHOP-driven transcriptional induction under ER stress, linking SESN2 to autophagic cytoprotection.

    Evidence Co-IP, CRISPR KO and rescue in rat cardiac model; ChIP of CHOP at SESN2 promoter

    PMID:31199952 PMID:31337142

    Open questions at the time
    • Whether SESN2-Parkin binding is direct unresolved
    • Quantitative contribution of CHOP versus other TFs not parsed
  8. 2020 Medium

    Demonstrated mitochondrial localization of SESN2 and mTORC1-independent regulation of mitochondrial function, and consolidated the GATOR2-GATOR1-Rag mechanism as the primary mTORC1-inhibitory route.

    Evidence Subcellular fractionation and live imaging; pathway analysis of GATOR2/GATOR1/Rag interactions

    PMID:32287270

    Open questions at the time
    • Mitochondrial submembrane location and import mechanism unknown
    • Direct structural basis of SESN2-GATOR2 binding not shown in these data
  9. 2021 High

    Broadened SESN2 regulatory inputs and outputs: C/EBPβ induction in atrophying muscle, AMPK-LKB1 complex promotion, p62-dependent NRF2 elevation, PERK-driven NRF2 epistasis, and JMJD3-mediated H3K27me3 repression.

    Evidence In vivo knockdown/overexpression, Co-IP, ChIP, siRNA/inhibitor epistasis across muscle, endothelial, and oocyte systems

    PMID:33117796 PMID:33231566 PMID:34429398 PMID:34923100 PMID:36994173

    Open questions at the time
    • Whether SESN2-AMPK-LKB1 contact is direct unresolved
    • Stoichiometry and selectivity of SESN2 toward distinct effectors unclear
  10. 2023 High

    Identified domain-level and effector-level specificity: two SESN2 domains separately engage Parkin and SQSTM1 for UPRmt-induced mitophagy, while mTORC1-independent branches act through PTPRD-STAT3, SHP-CREBH gluconeogenesis control, m6A/IGF2BP1 mRNA stabilization, and Rab7a/TFEB-dependent lysosomal trafficking.

    Evidence Domain mutagenesis, PINK1 epistasis, Sesn2-/- models, genetic inactivation, MeRIP-seq, IP-MS, ubiquitination and TFEB translocation assays

    PMID:36632468 PMID:37488285 PMID:38495179 PMID:39985075 PMID:40612680

    Open questions at the time
    • Boundaries and structures of the two functional domains not defined
    • How SESN2 lowers PTPRD mechanistically unknown
  11. 2024 High

    Extended SESN2 control of metabolism and redox: SETDB1/HP1β-mediated H3K9me3 repression, mTOR/HIF-1α-dependent glycolytic restraint, and leucine-induced SESN2-RPN2 signaling to GSK3β/β-catenin in myogenesis.

    Evidence ChIP, Co-IP, knockdown/inhibitor and rapamycin rescue in renal I/R, MCAO, and myoblast models

    PMID:38551359 PMID:39443993 PMID:40032632

    Open questions at the time
    • Direct SESN2-RPN2 functional consequence on leucine sensing unclear
    • Connection between mitochondrial SESN2 and glycolytic output incompletely defined
  12. 2025 High

    Resolved deubiquitinase-mediated stabilization and new direct interactors: KSHV vCyclin/OTUB1 stabilizes SESN2 to drive AMPK and lymphoma survival, SESN2 binds AKT1 to drive Ser473 phosphorylation and NRF2-dependent anti-ferroptosis, binds SCAP to block SREBP1 lipogenesis, and supports PRDX6-K209 lactylation/GPX4 redox defense.

    Evidence Reciprocal Co-IP, residue mutagenesis (vCyclin K74, PRDX6 K209R), ubiquitination and AKT1 phosphorylation assays, AAV in vivo rescue

    PMID:40822351 PMID:41196342 PMID:41966311 PMID:42105713

    Open questions at the time
    • Whether SESN2-AKT1 binding directly catalyzes Ser473 phosphorylation versus scaffolding unresolved
    • Structural basis of SESN2-SCAP interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single SESN2 protein selects among its many described effectors (GATOR2, ULK1/Parkin, AKT1, SCAP, AMPK-LKB1, RPN2) in a given cell state, and the structural basis for these competing interactions, remains unresolved.
  • No structural model distinguishing the effector-binding surfaces
  • Determinants of mitochondrial versus cytosolic SESN2 partitioning unknown
  • Quantitative hierarchy among parallel SESN2 outputs not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016209 antioxidant activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
AKT1GATOR2PARKINRPN2SCAPSETDB1SQSTM1ULK1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SESN2 (Hi95) is a stress-responsive gene transcriptionally induced by prolonged hypoxia, DNA damage (in a p53-dependent manner), and oxidative stress (p53-independent). Overexpression is toxic to many cell types, causing apoptosis or sensitization to stress, but conditional overexpression in MCF7 cells protects against hypoxia/glucose deprivation and H2O2-induced cell death. cDNA microarray, conditional overexpression (tet-off system), cell viability assays Oncogene Medium 12203114
2016 SESN2 suppresses prolonged NLRP3 inflammasome activation by inducing mitophagy in macrophages. Mechanistically, SESN2 (1) facilitates perinuclear clustering of mitochondria by mediating SQSTM1 aggregation and its binding to K63-linked ubiquitins on the mitochondrial surface ('mitochondrial priming'), and (2) activates autophagic machinery by increasing ULK1 protein levels. SESN2 expression in macrophages is induced by NOS2-derived NO. Sesn2-deficient mice show defective mitophagy and hyperactivation of inflammasomes with increased mortality in two sepsis models. Genetic knockout mice (two sepsis models), siRNA knockdown, immunofluorescence, co-immunoprecipitation, Western blot, ubiquitin binding assays Autophagy High 27337507
2016 SESN2 expression is transcriptionally induced by ISO treatment via a MAPK8/JNK1-JUN-dependent mechanism: ISO triggers MAPK8-dependent JUN activation and JUN binding to an AP-1 site in the SESN2 promoter, leading to SESN2 transcriptional induction that is required for autophagy induction in bladder cancer cells. Promoter-binding (ChIP/AP-1 reporter), siRNA knockdown, kinase inhibitors, Western blot Autophagy Medium 27171279
2016 UVB induces SESN2 expression in melanocytes through the p53 and AKT3 pathways; SESN2 negatively regulates UVB-induced DNA damage repair. UVA induces SESN2 through mitochondria (not Nrf2); SESN2 ablation increased UVA-induced Nrf2 induction and inhibited UVA-induced ROS production, identifying SESN2 as an upstream regulator of Nrf2. siRNA knockdown, pathway inhibitors, ROS measurement, DNA damage assays, immunoblot Photochemistry and photobiology Medium 27463837
2017 LSD1/KDM1A epigenetically represses SESN2 transcription by binding to its promoter. Pharmacological inhibition or selective ablation of LSD1 de-represses SESN2 expression, which then inhibits mTORC1 activity and promotes autophagy in neuroblastoma cells. SESN2 overexpression alone suffices to promote autophagy, and SESN2 loss reduces LSD1 inhibition-induced autophagy. ChIP (LSD1 binding to SESN2 promoter), LSD1 inhibitors (TCP, SP2509), siRNA/shRNA knockdown, mTORC1 activity assays, autophagy assays Oncogene High 28783174
2018 SESN2 facilitates Parkin translocation to defective mitochondria during mitophagy by interacting with ULK1 and assisting ULK1-mediated phosphorylation of Beclin1 at serine-14, which is required for Beclin1-Parkin binding prior to mitochondrial translocation. The trigger for SESN2 activation is mitochondrial superoxide. SESN2-mediated cytosolic Parkin-Beclin1 interaction is PINK1-independent, but mitochondrial translocation of Parkin is PINK1-dependent. Co-immunoprecipitation, siRNA knockdown, phosphorylation site mapping (S14-Beclin1), mitochondrial superoxide scavenging, mitophagy assays Scientific reports High 29330382
2018 RBX1 is an E3 ubiquitin ligase for SESN2 that mediates K48-linked ubiquitination of SESN2 upon prolonged mitochondrial damage (CCCP treatment), leading to SESN2 degradation and increased cell death. Downregulation of RBX1 stabilizes SESN2, reduces mitochondrial ROS, and reduces cell death. Co-immunoprecipitation, ubiquitination assays (K48-linkage), siRNA knockdown, cell viability assays Molecular and cellular biochemistry Medium 29294217
2018 SESN2 negatively regulates mTORC1 activity in an amino acid-sensing context in cow mammary epithelial cells. Amino acid starvation increases SESN2 expression; SESN2 overexpression suppresses mTORC1 activation, cell proliferation, and casein synthesis; SESN2 inhibition reverses these effects. Overexpression and inhibition experiments, mTORC1 pathway readouts (Western blot), cell proliferation assays Scientific reports Medium 29500367
2018 BDNF promotes ATF4 elevation in neurons in a TrkB-dependent, eIF2α-independent manner. ATF4 then directly mediates BDNF-induced transcriptional induction of SESN2, establishing BDNF→TrkB→ATF4→SESN2 as a neuroprotective signaling axis. Transcriptome analysis, ATF4 knockdown, TrkB signaling inhibition, Western blot, neuronal cultures Frontiers in molecular neuroscience Medium 29599707
2019 SESN2 interacts with Parkin and p62/SQSTM1, promotes accumulation of Parkin to mitochondria, and thereby alleviates doxorubicin-caused inhibition of Parkin-mediated mitophagy. SESN2 knockout (by sgRNA) inhibits Parkin-mediated mitophagy, increases cardiomyocyte apoptosis, and worsens mitochondrial dysfunction; ectopic SESN2 expression rescues these effects. Co-immunoprecipitation, CRISPR sgRNA knockout, mitophagy assays, electron microscopy, echocardiography, rat model Journal of molecular and cellular cardiology High 31199952
2019 ER stress-induced CHOP transcription factor directly binds the SESN2 promoter in colorectal cancer cells, increasing SESN2 expression, which then promotes autophagy. DHA + oxaliplatin enhance CHOP binding to the SESN2 promoter. Chromatin immunoprecipitation (CHOP binding to SESN2 promoter), Western blot, autophagy assays, in vitro and in vivo Cancers Medium 31337142
2020 SESN2 localizes to mitochondria, as demonstrated by subcellular fractionation and live-cell imaging experiments, and can directly regulate mitochondrial functions through mTORC1-independent mechanisms. Subcellular fractionation, mitochondrial localization experiments, live imaging PloS one Medium 32287270
2020 JMJD3 histone demethylase negatively regulates SESN2 transcription by reducing H3K27me3 tri-methylation in the SESN2 promoter region. JMJD3 inhibition or knockdown restores SESN2 expression and protects against doxorubicin-induced cardiomyopathy; JMJD3 overexpression aggravates cardiomyopathy in a SESN2-dependent manner. ChIP (H3K27me3 at SESN2 promoter), JMJD3 knockdown/overexpression, SESN2 rescue overexpression, Western blot, cardiac functional assays Frontiers in cell and developmental biology High 33117796
2021 SESN2 is transcriptionally induced by the ER stress-activated transcription factor C/EBPβ in denervated skeletal muscle. Once induced, SESN2 inhibits mTORC1 to attenuate ER stress, and also activates autophagic machinery to facilitate SQSTM1/p62 aggregation on the mitochondrial surface, promoting mitophagy and protecting against muscle atrophy. Knockdown and overexpression (AAV delivery), denervation mouse model, Western blot, electron microscopy, immunofluorescence, mTORC1 activity assays Cell death & disease Medium 34429398
2021 SESN2 promotes the formation of a complex between AMPK and LKB1 (as demonstrated by immunoprecipitation), thereby facilitating AMPK-T172 phosphorylation. This mechanism underlies globular adiponectin-induced AMPK activation and insulin sensitization in skeletal muscle; these effects are absent in SESN2-/- mice. Co-immunoprecipitation, SESN2 knockout mice, AMPK phosphorylation assays, insulin signaling readouts Sports medicine and health science Medium 36994173
2021 SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex, preventing GATOR2's inhibitory effect on GATOR1, which stimulates GTPase activity of RagA/B, preventing mTORC1 lysosomal translocation and activation. This pathway is established as SESN2's primary mTORC1-inhibitory mechanism. Pathway analysis, protein interaction (GATOR2/GATOR1/Rag GTPases), cited as established mechanism in review context within original research paper PloS one Medium 32287270
2021 SESN2 increases Nrf2 protein expression by enhancing p62-dependent autophagy in endothelial progenitor cells treated with angiotensin II, providing a mechanism linking SESN2 to antioxidant defense via the Keap1/Nrf2 axis. Western blot, siRNA knockdown of Nrf2, p62 autophagy assays, immunofluorescence, EPCs from human umbilical cord blood Aging Medium 33231566
2021 PERK pathway upregulation increases SESN2 expression in porcine oocytes. SESN2 acts upstream of NRF2: SESN2 siRNA knockdown blocks NRF2 nuclear activation, while NRF2 inhibition does not affect SESN2 protein levels. SESN2 deficiency blocks nuclear NRF2 activity and disrupts spindle assembly during oocyte maturation. siRNA knockdown, Western blot, immunofluorescence, NRF2 inhibitor, porcine oocyte IVM Free radical biology & medicine Medium 34923100
2023 UPRmt upregulates SESN2 through the Eif2ak4/eIF2α/Atf4 transcriptional axis. SESN2 then promotes translocation of cytosolic Parkin and SQSTM1 to defective mitochondria using two functional domains required for interacting with Parkin and SQSTM1, respectively. SQSTM1 translocation to mitochondria is Parkin-dependent. SESN2-mediated cytosolic Parkin-SQSTM1 interaction is PINK1-independent, while mitochondrial translocation requires PINK1. siRNA/gene silencing, domain mutagenesis, co-immunoprecipitation, Sesn2-/- mice (intervertebral disc degeneration model), mitophagy assays International journal of biological sciences High 36632468
2023 p53-regulated SESN2 suppresses STAT3 activity by downregulating the PTPRD phosphatase (responsible for STAT3 dephosphorylation), thereby regulating cell proliferation and death via an mTORC1-independent mechanism. SESN1&2 inactivation in A549 cells accelerates proliferation and confers drug resistance without affecting mTORC1, but stimulates STAT3. SESN1&2 double inactivation in A549 cells, STAT3 phosphorylation assays, PTPRD expression analysis, cell proliferation and death assays Cell communication and signaling Medium 39985075
2023 Melatonin-induced SESN2 inhibits hepatic gluconeogenesis via a SESN2-SHP signaling cascade that competes with BTG2 and inhibits CREBH-mediated gluconeogenic gene transcription, suppressing the CRBN-BTG2-CREBH signaling axis. Sesn2 and Shp silencing mice, primary hepatocytes, gene expression analysis, rescue experiments Experimental & molecular medicine Medium 37488285
2023 FTO demethylase reduces m6A methylation of SESN2 mRNA, decreasing its stability. FTO deficiency promotes binding of IGF2BP1 to SESN2 mRNA at exon 9 m6A modification sites, enhancing SESN2 mRNA stability and elevating SESN2 protein expression, which activates AMPK-mTOR-dependent autophagy in NSCLC cells. m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA stability assays, IGF2BP1 RIP, site-specific m6A mapping, SESN2 knockdown Heliyon Medium 38495179
2024 SETDB1 histone methyltransferase collaborates with heterochromatin protein HP1β to deposit H3K9me3 on the SESN2 promoter, thereby repressing SESN2 expression. SESN2 mediates SETDB1's regulation of mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury. ChIP (H3K9me3 at SESN2 promoter), co-immunoprecipitation (SETDB1-HP1β), SETDB1 knockdown and pharmacological inhibition, in vivo and in vitro I/R models BMC biology High 39443993
2024 SESN2 promotes the interaction between SESN2 and RPN2 (ribophorin II) in response to leucine binding. RPN2 overexpression activates the GSK3β/β-catenin pathway (increasing nuclear β-catenin), whereas RPN2 knockdown combined with leucine rescues GSK3β phosphorylation effects, supporting SESN2-mediated promotion of C2C12 myoblast differentiation via the GSK3β/β-catenin pathway. Co-immunoprecipitation (SESN2-RPN2 interaction), RPN2 overexpression and knockdown, RNA sequencing, Western blot, β-catenin nuclear translocation assays, in vivo muscle injury model Journal of the science of food and agriculture Medium 38551359
2024 SESN2 knockdown in brain tissue increases mTOR/HIF-1α pathway activity and enhances glycolysis (increased HK2, PFKM, PKM1, PKM2, GLUT1, and lactate levels), worsening cerebral ischemia-reperfusion injury. mTOR inhibition with rapamycin reverses these effects, demonstrating that SESN2 regulates glycolysis via mTOR/HIF-1α. Lentiviral SESN2 shRNA knockdown, MCAO mouse model, rapamycin rescue, Western blot, immunofluorescence, lactate assay CNS neuroscience & therapeutics Medium 40032632
2025 KSHV-encoded vCyclin (a Cyclin D homolog) directly interacts with SESN2 and recruits the deubiquitinase OTUB1, blocking SESN2 polyubiquitination and proteasomal degradation, thereby stabilizing and upregulating SESN2. vCyclin lysine at residue 74 is crucial for cytosolic localization, OTUB1 recruitment, and SESN2 upregulation. Stabilized SESN2 activates AMPK to support survival of KSHV-driven primary effusion lymphoma cells. Co-immunoprecipitation (vCyclin-SESN2-OTUB1 complex), site-directed mutagenesis (K74 of vCyclin), ubiquitination assays, AMPK activity assays, cell survival assays Proceedings of the National Academy of Sciences of the United States of America High 41196342
2025 SESN2 directly binds AKT1 and promotes its phosphorylation at Ser473, which activates NRF2 nuclear localization to inhibit ferroptosis. Hepatocyte-specific AAV-mediated SESN2 knockdown abolishes the hepatoprotective effects of Yakuchinone A, establishing SESN2 as its primary pharmacological target in hepatic ischemia-reperfusion injury. AAV-mediated hepatocyte-specific overexpression/knockdown in vivo, co-immunoprecipitation (SESN2-AKT1), AKT1 phosphorylation assays, NRF2 nuclear translocation, rescue-of-function experiments International immunopharmacology Medium 42105713
2025 SESN2 interacts with SCAP (SREBP cleavage-activating protein) to deactivate SREBP1-mediated transcription of lipogenic enzymes in chondrocytes, and overexpression of Sesn2 in mice prevents obesity-related cartilage lipogenesis and OA progression. Co-immunoprecipitation (SESN2-SCAP), SREBP1 target gene assays, AAV-mediated Sesn2 overexpression in DMM mouse model, Western blot, histology iScience Medium 40822351
2025 SESN2 deficiency reduces PRDX6 K209 lactylation, a modification required for PRDX6-mediated redox homeostasis; quantitative co-immunoprecipitation showed PRDX6 interacts with GPX4, and this interaction is markedly weakened by K209R mutation. Re-expression of wild-type PRDX6 but not K209R mutant rescues SESN2 deficiency-induced oxidative stress and ferroptosis in granulosa cells. Quantitative co-immunoprecipitation, site-directed mutagenesis (K209R), lactylation analysis, SESN2 deficiency models (in vitro/in vivo), rescue experiments Free radical biology & medicine Medium 41966311
2023 SESN2 overexpression promotes MVB (multivesicular body) degradation by inhibiting Rab-7a ubiquitination, thereby promoting autophagosome-lysosome fusion. Additionally, SESN2 promotes TFEB nuclear translocation via the mTOR pathway to enhance lysosomal function, reducing exosome secretion from BSA-injured tubular cells. RNA-seq, IP-MS, Western blot, TFEB nuclear translocation assay, Rab-7a ubiquitination assay, SESN2 overexpression in HK2 cells International journal of biological sciences Medium 40612680
2018 miR-182-5p directly represses SESN2 expression by targeting its 3'-UTR (validated by luciferase reporter and RNP-IP), and ATO-mediated suppression of miR-182-5p leads to stabilization of SESN2 mRNA through AGO2-dependent gene silencing relief. Luciferase reporter assay (SESN2 3'UTR), ribonucleoprotein immunoprecipitation (RNP-IP/AGO2), miR-182-5p mimic transfection, mRNA stability assays Oncotarget Medium 29662624

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 318 12203114
2016 SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy 240 27337507
2019 SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function. Journal of molecular and cellular cardiology 90 31199952
2016 SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers. Autophagy 85 27171279
2021 Long noncoding RNA p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway. Pharmacological research 83 34601081
2020 Hexavalent chromium induced heart dysfunction via Sesn2-mediated impairment of mitochondrial function and energy supply. Chemosphere 74 33049514
2017 Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway. Oncogene 72 28783174
2023 miR-484 mediates oxidative stress-induced ovarian dysfunction and promotes granulosa cell apoptosis via SESN2 downregulation. Redox biology 70 36963287
2023 Empagliflozin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Modulating Sesn2/AMPK/Nrf2 Signaling and Targeting Ferroptosis and Autophagy. International journal of molecular sciences 60 37298433
2018 SESN2 facilitates mitophagy by helping Parkin translocation through ULK1 mediated Beclin1 phosphorylation. Scientific reports 57 29330382
2022 Icariin protects podocytes from NLRP3 activation by Sesn2-induced mitophagy through the Keap1-Nrf2/HO-1 axis in diabetic nephropathy. Phytomedicine : international journal of phytotherapy and phytopharmacology 50 35247669
2019 Knockdown of LSD1 meliorates Ox-LDL-stimulated NLRP3 activation and inflammation by promoting autophagy via SESN2-mesiated PI3K/Akt/mTOR signaling pathway. Life sciences 42 31351969
2018 SESN2 negatively regulates cell proliferation and casein synthesis by inhibition the amino acid-mediated mTORC1 pathway in cow mammary epithelial cells. Scientific reports 40 29500367
2019 Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer. Cancers 37 31337142
2016 Distinct Role of Sesn2 in Response to UVB-Induced DNA Damage and UVA-Induced Oxidative Stress in Melanocytes. Photochemistry and photobiology 37 27463837
2021 SESN2 protects against denervated muscle atrophy through unfolded protein response and mitophagy. Cell death & disease 36 34429398
2017 Sesn2 gene ablation enhances susceptibility to gentamicin-induced hair cell death via modulation of AMPK/mTOR signaling. Cell death discovery 36 28580173
2021 Molecular pathways in sepsis-induced cardiomyocyte pyroptosis: Novel finding on long non-coding RNA ZFAS1/miR-138-5p/SESN2 axis. Immunology letters 33 34271014
2020 Sulforaphane attenuates hexavalent chromium-induced cardiotoxicity via the activation of the Sesn2/AMPK/Nrf2 signaling pathway. Metallomics : integrated biometal science 33 33159781
2021 SESN2/NRF2 signaling activates as a direct downstream regulator of the PERK pathway against endoplasmic reticulum stress to improve the in vitro maturation of porcine oocytes. Free radical biology & medicine 32 34923100
2020 Mitochondrial localization of SESN2. PloS one 30 32287270
2020 Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression. Frontiers in cell and developmental biology 27 33117796
2023 Sesn2 Serves as a Regulator between Mitochondrial Unfolded Protein Response and Mitophagy in Intervertebral Disc Degeneration. International journal of biological sciences 25 36632468
2016 Oleanolic acid attenuates liver ischemia reperfusion injury by HO-1/Sesn2 signaling pathway. Hepatobiliary & pancreatic diseases international : HBPD INT 25 27733322
2015 An ShRNA Based Genetic Screen Identified Sesn2 as a Potential Tumor Suppressor in Lung Cancer via Suppression of Akt-mTOR-p70S6K Signaling. PloS one 24 25962159
2023 Resistance exercise alleviates the prefrontal lobe injury and dysfunction by activating SESN2/AMPK/PGC-1α signaling pathway and inhibiting oxidative stress and inflammation in mice with myocardial infarction. Experimental neurology 23 37788754
2022 Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling. The Journal of nutritional biochemistry 21 35643285
2021 Effects of chitooligosaccharide-zinc on the ovarian function of mice with premature ovarian failure via the SESN2/NRF2 signaling pathway. Chinese journal of natural medicines 21 34688462
2024 Tangeretin alleviates inflammation and oxidative response induced by spinal cord injury by activating the Sesn2/Keap1/Nrf2 pathway. Phytotherapy research : PTR 19 39054118
2021 OncomiR miR-182-5p Enhances Radiosensitivity by Inhibiting the Radiation-Induced Antioxidant Effect through SESN2 in Head and Neck Cancer. Antioxidants (Basel, Switzerland) 19 34829679
2018 RBX1-mediated ubiquitination of SESN2 promotes cell death upon prolonged mitochondrial damage in SH-SY5Y neuroblastoma cells. Molecular and cellular biochemistry 19 29294217
2022 SESN2 prevents the slow-to-fast myofiber shift in denervated atrophy via AMPK/PGC-1α pathway. Cellular & molecular biology letters 18 35945510
2020 Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway. Aging 17 33231566
2018 Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) in Neurons and Promotes ATF4-Dependent Induction of Sesn2. Frontiers in molecular neuroscience 17 29599707
2018 Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation of SESN2. Oncotarget 16 29662624
2023 tRF-20-S998LO9D inhibits endometrial carcinoma by upregulating SESN2. Epigenomics 15 36803014
2025 p53-regulated SESN1 and SESN2 regulate cell proliferation and cell death through control of STAT3. Cell communication and signaling : CCS 13 39985075
2024 Resistance exercise preconditioning prevents disuse muscle atrophy by inhibiting apoptosis and protein degradation via SESN2 in C57BL/6J mice. Biochimica et biophysica acta. Molecular basis of disease 12 38432454
2022 Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity. Cells 12 36010689
2021 Exercise improves lipid metabolism disorders induced by high-fat diet in a SESN2/JNK-independent manner. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 12 34038646
2022 Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2. Sports medicine and health science 11 36994173
2019 Genetic association of DDIT3, RPL23A, SESN2 and NR4A1 genes with milk yield and composition in dairy cattle. Animal genetics 11 30815908
2024 N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells. Inflammation 10 39037665
2023 Solanine Represses Gastric Cancer Growth by Mediating Autophagy Through AAMDC/MYC/ATF4/Sesn2 Signaling Pathway. Drug design, development and therapy 10 36789094
2023 Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway. Experimental & molecular medicine 9 37488285
2023 Gallic acid as a Sestrin (SESN2) activator and potential obesity therapeutic agent: A molecular docking study. Gene 9 37536400
2025 Knockdown of SESN2 Exacerbates Cerebral Ischemia-Reperfusion Injury Through Enhancing Glycolysis via the mTOR/HIF-1α Pathway. CNS neuroscience & therapeutics 8 40032632
2023 Circular RNA SESN2 aggravates gestational trophoblast cell damage induced by high glucose by binding to IGF2BP2. Molecular reproduction and development 8 36623264
2023 SESN2-Mediated AKT/GSK-3β/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High-Fat Diet-Induced Obese Mice. Antioxidants & redox signaling 8 37265150
2022 2,3,4',5‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside ameliorates gentamicin‑induced ototoxicity by modulating autophagy via Sesn2/AMPK/mTOR signaling. International journal of molecular medicine 8 35348190
2025 Cyanidin-3-O-glucoside mitigates Staphylococcus aureus-induced mastitis by suppressing inflammatory responses and Ferroptosis mediated by SESN2/Nrf2. International immunopharmacology 7 40394793
2024 Effects of gallic acid and physical training on liver damage, force, and anxiety in obese mice: Hepatic modulation of Sestrin 2 (SESN2) and PGC-α expression. Gene 7 38788813
2023 MicroRNA-34a-5p promotes the progression of osteoarthritis secondary to developmental dysplasia of the hip by restraining SESN2-induced autophagy. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 7 37291947
2023 Sestrin2 protects against hypoxic nerve injury by regulating mitophagy through SESN2/AMPK pathway. Frontiers in molecular biosciences 7 37808523
2023 Melatonin Ameliorates Ovarian Hyperstimulation Syndrome (OHSS) through SESN2 Regulated Antiapoptosis. Obstetrics and gynecology international 7 37937274
2025 MK8722 alleviates osteoarthritis by activating Sesn2 and transcriptionally upregulating BNIP3 to promote mitophagy and inhibit chondrocyte ferroptosis. Journal of advanced research 6 41077348
2024 Shionone Inhibits Glomerular Fibirosis by Suppressing NLRP3 Related Inflammasome though SESN2-NRF2/ HO-1 Pathway. Diabetes & metabolism journal 6 39192821
2022 Clinical application of RUBCN/SESN2 mediated inhibition of autophagy as biomarkers of diabetic kidney disease. Molecular medicine (Cambridge, Mass.) 6 36476132
2022 SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells. Cells 6 36611970
2025 Exercise-induced Sesn2 mediates autophagic flux to alleviate neural damage after ischemic stroke in mice. Experimental neurology 5 39904418
2025 Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc-/GPX4 pathway. Frontiers in genetics 5 39944356
2024 FTO-mediated autophagy inhibition promotes non-small cell lung cancer progression by reducing the stability of SESN2 mRNA. Heliyon 5 38495179
2024 Inhibition of Sesn2 has negative regulatory effects on the myogenic differentiation of C2C12 myoblasts. Molecular biomedicine 5 39117956
2023 SESN2 attenuates sevoflurane-induced cognitive impairment and neuroinflammation in rats. Experimental brain research 5 38129329
2024 The C/EBPβ-SESN2 Axis Promotes M2b Macrophage Polarization Induced by T.cp-MIF to Suppress Inflammation in Thelazia Callipaeda Infection. Inflammation 4 39215929
2024 Mir-615-3p promotes osteosarcoma progression via the SESN2/AMPK/mTOR pathway. Cancer cell international 4 39702297
2023 Farnesoid X Receptor (FXR) Regulates mTORC1 Signaling and Autophagy by Inhibiting SESN2 Expression. Molecular nutrition & food research 4 36715418
2023 chi-miR-130b-3p regulates the ZEA-induced oxidative stress damage through the KEAP1/NRF2 signaling pathway by targeting SESN2 in goat GCs. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 37773760
2025 CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice. Journal of cachexia, sarcopenia and muscle 3 41030226
2024 Hyperglycemia exacerbates cerebral ischemia/reperfusion injury by up-regulating autophagy through p53-Sesn2-AMPK pathway. Neuroscience letters 3 38191089
2024 Leu promotes C2C12 cell differentiation by regulating the GSK3β/β-catenin signaling pathway through facilitating the interaction between SESN2 and RPN2. Journal of the science of food and agriculture 3 38551359
2024 SETDB1 targeting SESN2 regulates mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury. BMC biology 3 39443993
2023 Resveratrol Promotes Gluconeogenesis by Inhibiting SESN2-mTORC2-AKT Pathway in Calf Hepatocytes. The Journal of nutrition 3 37182694
2021 A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1. Frontiers in cell and developmental biology 3 34249922
2020 Copy Number Alterations in Papillary Thyroid Carcinomas: Does Loss of SESN2 Have a Role in Age-related Different Prognoses? Cancer genomics & proteomics 3 32859642
2026 Galangin Mitigates Alcohol-Induced Intestinal Damage by Suppressing Ferroptosis via the SESN2/KEAP1/NRF2 Pathway in Mice and Caco-2 Cells. Journal of agricultural and food chemistry 2 41605867
2025 Serum Hsa-miR-4695-5p Serves as a Novel Diagnostic Biomarker for Acute Severe Pancreatitis and Exacerbates Pathological Injury by Targeting SESN2. Digestive diseases and sciences 2 40601221
2025 SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway. International journal of biological sciences 2 40612680
2025 SREBF1-mediated SND1 transcriptional activation promotes prostate cancer progression via MTDH interaction through the SESN2/AMPK/mTOR axis. Journal of translational medicine 2 40775338
2025 Beneficial effects of dihydrocapsaicin on paraquat-induced acute kidney injury: role of Sox9/Sesn2 axis-mediated autophagy. Ecotoxicology and environmental safety 2 40834759
2025 Lactoferrin-cyanidin-3-glucoside nanoparticles alleviate inflammation and oxidative stress via Sesn2/Nrf2 activation in mastitis. Materials today. Bio 2 41281654
2024 DNA methylation-driven gene FAM3D promotes colorectal cancer growth via the ATF4-SESN2-mTORC1 pathway. Aging 2 39388305
2018 [Sestrin 2(SESN2) promotes primary resistance to sorafenib by activating AKT in hepatocellular carcinoma cells]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 2 30043734
2025 Direct scavenging of ROS by S-PPE NP reduces oxidative stress-induced stimulation of the SESN2/AMPK/KIM-1 pathway in acute kidney injury. Renal failure 1 40485171
2025 SESN2 maintains cartilage homeostasis by SREBP1-mediated lipid metabolism during osteoarthritis progression. iScience 1 40822351
2025 Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model. Cureus 1 40842769
2025 Polylactic acid microplastics and fish species intestinal inflammation risk: Associated with mitochondrial function mediated by Sesn2/Nrf2 pathway. Environment international 1 41086475
2025 Rhoifolin prevents herpes simplex virus encephalitis by modulating SESN2 to regulate the Keap1/Nrf2 and AMPK/Nox pathways to inhibit neuro-oxidative damage in mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 41351982
2024 Lysine specific demethylase 1 inhibits sodium arsenite activation of HSCs by regulating SESN2/AMPK/ULK1 signaling pathway activity. Environmental toxicology 1 38477077
2020 WITHDRAWN: GAS5 enhances natural killer cell-mediated killing by promoting ubiquitination of SESN2 in prostate cancer cells. Experimental and molecular pathology 1 32511948
2026 Inhibitory effect of blestriarene C on triple-negative breast cancer: Inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis. Chinese medical journal 0 41527177
2026 SESN2 suppresses ferroptosis in polycystic ovary syndrome by maintaining PRDX6 K209 lactylation. Free radical biology & medicine 0 41966311
2026 Yakuchinone A alleviates hepatic ischemia-reperfusion injury in aging livers via the SESN2/AKT1/NRF2 pathway. International immunopharmacology 0 42105713
2026 The FOXM1-SESN2 axis maintains redox homeostasis and protects esophageal squamous carcinoma cells from oxidative stress. Biochemistry and biophysics reports 0 42110337
2025 Zinc finger transcription factor ZNF384 mitigates LPS-induced ferroptosis and inflammation in lung epithelial cells by activating SESN2-mediated autophagy. Toxicology in vitro : an international journal published in association with BIBRA 0 40374019
2025 SESN2 mediates resistance training-induced improvements in exercise performance and energy metabolism in C57BL/6J mice. Experimental cell research 0 40425138
2025 A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth. Proceedings of the National Academy of Sciences of the United States of America 0 41196342
2025 Protective Effect of SESN2 on Glutamate Neurotoxicity via Keap1-Nrf2 Pathway-Mediated Mitophagy. Journal of biochemical and molecular toxicology 0 41370333
2025 Mesenchymal stromal cells preserve alveolar macrophages by inducing Sesn2 expression via lactic acid production in a mouse model of bleomycin-induced lung injury. Cell transplantation 0 41383119
2024 SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy. Cell biochemistry and biophysics 0 39417977

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