Affinage

SESN2

Sestrin-2 · UniProt P58004

Length
480 aa
Mass
54.5 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SESN2 is a stress-inducible metabolic regulator that integrates diverse cellular stress signals into coordinated control of mTORC1 inhibition, AMPK activation, autophagy/mitophagy, NRF2-mediated antioxidant defense, and lipid metabolism. Transcriptionally induced by p53 (DNA damage), ATF4/C/EBPβ/CHOP (ER and metabolic stress), AP-1/JNK (oxidative stress), and BDNF/TrkB (neurotrophin signaling), and epigenetically regulated by LSD1, JMJD3, and SETDB1/HP1β via histone modifications at its promoter, SESN2 acts as a scaffold that facilitates LKB1–AMPK complex formation to activate AMPK, promotes ULK1-mediated Beclin1-S14 phosphorylation to enable Parkin/SQSTM1 translocation to mitochondria for mitophagy, interacts with KEAP1 to liberate NRF2 for nuclear translocation, and binds SCAP to block SREBP1-driven lipogenesis (PMID:12203114, PMID:36994173, PMID:29330382, PMID:36632468, PMID:41605867, PMID:40822351). SESN2 protein turnover is governed by RBX1-mediated K48-linked ubiquitination leading to proteasomal degradation, counteracted by OTUB1-dependent deubiquitination recruited by KSHV vCyclin, while SESN2 mRNA stability is modulated by m6A modifications (FTO/IGF2BP1) and miRNA-mediated silencing (miR-182-5p, miR-138-5p) (PMID:29294217, PMID:41196342, PMID:38495179, PMID:29662624). Additionally, SESN2 suppresses STAT3 signaling by maintaining PTPRD phosphatase expression and inhibits ferroptosis through upregulation of System Xc⁻/GPX4 (PMID:39985075, PMID:39944356).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    The identification of SESN2 (Hi95) as a stress-responsive gene induced by hypoxia, DNA damage, and oxidative stress — with p53-dependent and p53-independent arms — established it as a convergent stress effector rather than a single-pathway target.

    Evidence cDNA microarray and conditional overexpression in MCF7 cells under multiple stress conditions

    PMID:12203114

    Open questions at the time
    • Downstream effector mechanism unknown at this stage
    • No interacting partners identified
    • p53-independent induction pathway not molecularly defined
  2. 2016 High

    Demonstration that SESN2 promotes mitophagy by mediating SQSTM1/p62 aggregation on ubiquitinated mitochondria and stabilizing ULK1 resolved how SESN2 suppresses NLRP3 inflammasome activation in macrophages, connecting stress-induced SESN2 to organelle quality control.

    Evidence Sesn2 knockout mice in two sepsis models, co-immunoprecipitation, macrophage inflammasome assays

    PMID:27337507

    Open questions at the time
    • Direct SESN2–ULK1 binding interface not mapped
    • Relative contribution of SQSTM1 aggregation versus ULK1 stabilization not quantified
  3. 2016 High

    Identification of AP-1/JNK-dependent transcriptional activation of SESN2 via a JUN-binding site in the SESN2 promoter expanded the repertoire of upstream inducers beyond p53, linking oxidative and oncogenic stress signals to SESN2-dependent autophagy.

    Evidence ChIP and luciferase reporter assays in bladder cancer cells with JNK1 inhibitors and siRNA knockdown

    PMID:27171279

    Open questions at the time
    • Whether AP-1 cooperates with or substitutes for p53 at the SESN2 promoter not determined
    • Other AP-1 family members not tested
  4. 2017 High

    Discovery that LSD1 directly binds and represses the SESN2 promoter revealed the first epigenetic layer controlling SESN2 expression, and that LSD1 inhibition-induced autophagy requires SESN2 established epistasis between chromatin remodeling and mTORC1 inhibition.

    Evidence ChIP for LSD1 at SESN2 promoter, LSD1 inhibitors/shRNA, SESN2 knockdown rescue in neuroblastoma cells

    PMID:28783174

    Open questions at the time
    • Specific histone mark(s) demethylated by LSD1 at the SESN2 promoter not characterized in this study
    • Later work showed context-dependent LSD1 effects on H3K4me1/2 at the SESN2 promoter
  5. 2018 High

    Mapping the SESN2–ULK1–Beclin1 axis showed that SESN2 assists ULK1-mediated phosphorylation of Beclin1 at Ser-14, which enables cytosolic Beclin1–Parkin interaction and subsequent PINK1-dependent mitochondrial Parkin translocation, dissecting mitophagy into PINK1-independent and PINK1-dependent steps.

    Evidence Co-immunoprecipitation, SESN2 siRNA, ULK1 interaction assays, PINK1 epistasis in multiple cell types

    PMID:29330382

    Open questions at the time
    • Whether SESN2 directly bridges ULK1 and Beclin1 or acts allosterically not resolved
    • Structural basis of SESN2–ULK1 interaction unknown
  6. 2018 Medium

    Identification of RBX1 as an E3 ubiquitin ligase that mediates K48-linked polyubiquitination and degradation of SESN2 upon prolonged mitochondrial damage revealed how SESN2 protein levels are negatively regulated post-translationally.

    Evidence Co-immunoprecipitation, K48-linkage-specific ubiquitination assay, RBX1 siRNA stabilization of SESN2

    PMID:29294217

    Open questions at the time
    • Specific lysine residues on SESN2 targeted by RBX1 not identified
    • CRL complex composition (Cullin partner, substrate adaptor) not defined
    • Not independently replicated
  7. 2018 Medium

    Establishing that BDNF induces SESN2 through TrkB-mediated ATF4 upregulation (independent of eIF2α) placed SESN2 downstream of neurotrophin signaling, broadening its role beyond canonical stress pathways.

    Evidence ATF4 knockdown blocking BDNF-induced SESN2 in neuronal cultures, TrkB inhibitors, transcriptomics

    PMID:29599707

    Open questions at the time
    • Whether ATF4 binds directly to the SESN2 promoter in this context not shown by ChIP
    • Functional neuroprotective readout downstream of SESN2 not fully defined
  8. 2019 High

    Demonstration that SESN2 physically interacts with both Parkin and p62/SQSTM1 and that SESN2 knockout inhibits Parkin-mediated mitophagy causing cardiomyocyte apoptosis confirmed SESN2 as an essential scaffold in cardiac mitophagy, extending findings from macrophages to the heart.

    Evidence sgRNA SESN2 knockout, co-immunoprecipitation with Parkin and p62, mitophagy assays, echocardiography in doxorubicin cardiotoxicity model

    PMID:31199952

    Open questions at the time
    • Whether SESN2 forms a ternary complex with Parkin and p62 simultaneously versus sequential interactions not resolved
  9. 2020 Medium

    Direct demonstration of SESN2 localization on mitochondria by subcellular fractionation provided a physical basis for its role in mitophagy and mitochondrial quality control beyond mTORC1 signaling.

    Evidence Mitochondrial fractionation, subcellular localization assays, live-cell imaging

    PMID:32287270

    Open questions at the time
    • Mechanism of mitochondrial targeting (signal sequence or protein interaction) not identified
    • Whether localization is constitutive or stress-dependent not fully resolved
  10. 2020 High

    Discovery that JMJD3 represses SESN2 by reducing H3K27me3 at its promoter, and that SETDB1/HP1β deposits H3K9me3 to repress SESN2, defined two independent repressive epigenetic marks controlling SESN2 transcription and showed their functional relevance in cardioprotection and renal protection.

    Evidence ChIP for H3K27me3 and H3K9me3 at SESN2 promoter, JMJD3/SETDB1 knockdown/overexpression rescue, in vivo cardiac and renal models

    PMID:33117796 PMID:39443993

    Open questions at the time
    • Interplay between multiple epigenetic regulators (LSD1, JMJD3, SETDB1) at the SESN2 promoter not studied in a unified system
    • Whether these marks are mutually exclusive or co-occur not addressed
  11. 2022 Medium

    Showing that SESN2 promotes LKB1–AMPK complex formation and is required for LKB1-mediated AMPK-T172 phosphorylation defined the molecular mechanism by which SESN2 activates AMPK, resolving a long-standing link between SESN2 and energy sensing.

    Evidence SESN2−/− mice, immunoprecipitation of AMPK–LKB1 complex, overexpression/inhibition in C2C12 myotubes

    PMID:36994173

    Open questions at the time
    • Whether SESN2 acts as a direct scaffold bridging LKB1 and AMPK or alters their conformations not determined
    • Single-lab finding awaits independent replication
  12. 2023 High

    Domain-deletion mutagenesis revealed that two distinct SESN2 functional domains mediate interaction with Parkin and SQSTM1 respectively, and confirmed the UPRmt–eIF2α–ATF4 axis as an upstream inducer, integrating mitochondrial stress signaling with SESN2-dependent mitophagy.

    Evidence Domain deletion mutagenesis, co-IP, Sesn2−/− mice in intervertebral disc degeneration model, PINK1 epistasis

    PMID:36632468

    Open questions at the time
    • Structural resolution of SESN2 domains binding Parkin and p62 lacking
    • Whether these domains function independently or cooperatively not determined
  13. 2023 Medium

    Identification of SESN2–SCAP interaction that blocks SREBP1 processing and lipogenic gene expression expanded SESN2 function beyond autophagy/mTORC1 into direct metabolic lipid regulation, with in vivo relevance in osteoarthritis cartilage protection.

    Evidence Co-immunoprecipitation of SESN2–SCAP, AAV-mediated overexpression in DMM mouse model

    PMID:40822351

    Open questions at the time
    • Whether SESN2–SCAP interaction is direct or mediated by a complex not established
    • Binding domain on SESN2 for SCAP not mapped
  14. 2023 Medium

    Discovery that SESN2 maintains PTPRD phosphatase expression to suppress STAT3 activation through an mTORC1-independent mechanism identified a novel tumor-suppressive axis and demonstrated SESN2 operates through diverse, non-overlapping effector pathways.

    Evidence SESN1/2 double KO in A549 cells, STAT3 phosphorylation and PTPRD expression analysis

    PMID:39985075

    Open questions at the time
    • Mechanism by which SESN2 maintains PTPRD expression not defined
    • Whether SESN2 directly regulates PTPRD transcription or protein stability unknown
  15. 2024 Medium

    Demonstration that FTO-mediated m6A demethylation destabilizes SESN2 mRNA while IGF2BP1 binds m6A-modified SESN2 mRNA to stabilize it revealed an epitranscriptomic layer of SESN2 regulation, adding post-transcriptional control to the known transcriptional and post-translational mechanisms.

    Evidence MeRIP-seq identifying m6A at exon 9, IGF2BP1 RIP, mRNA stability assays upon FTO knockdown in NSCLC cells

    PMID:38495179

    Open questions at the time
    • Whether other m6A readers (e.g., YTHDF proteins) also regulate SESN2 mRNA not tested
    • Functional relevance of exon 9 m6A site versus other potential sites not resolved
  16. 2025 High

    Discovery that KSHV vCyclin directly binds SESN2 and recruits OTUB1 deubiquitinase to block its polyubiquitination and proteasomal degradation revealed how a viral oncogene hijacks SESN2 stabilization to activate AMPK for lymphoma cell survival, and provided the first identified deubiquitinase for SESN2.

    Evidence Co-immunoprecipitation of vCyclin–SESN2–OTUB1, site-directed mutagenesis (vCyclin K74), ubiquitination assay in PEL cells

    PMID:41196342

    Open questions at the time
    • Whether OTUB1 regulates endogenous SESN2 turnover in the absence of vCyclin not tested
    • Relationship between OTUB1 and RBX1-mediated degradation not examined
  17. 2025 Medium

    Confirmation that SESN2 physically interacts with KEAP1 to promote KEAP1–NRF2 dissociation and NRF2 nuclear translocation provided a direct mechanism for SESN2-mediated antioxidant defense and ferroptosis suppression, consolidating prior observations of SESN2–NRF2 epistasis.

    Evidence Co-immunoprecipitation of SESN2–KEAP1, SESN2 siRNA abolishing galangin-induced NRF2 activation, in vivo mouse model

    PMID:41605867

    Open questions at the time
    • Whether SESN2 competes with NRF2 for the same KEAP1 binding site not structurally resolved
    • Stoichiometry of SESN2–KEAP1 interaction not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and quantitative model of how SESN2 simultaneously engages its many partners (GATOR2, LKB1/AMPK, ULK1/Beclin1, Parkin/SQSTM1, KEAP1, SCAP) — whether through distinct domain-specific interactions or mutually exclusive complexes — remains unresolved, as does the relative contribution of each effector arm to SESN2's protective functions in different tissues.
  • No high-resolution structure of full-length SESN2 in complex with effector partners
  • Relative flux through mTORC1, AMPK, mitophagy, NRF2, and SREBP1 arms not quantified in any single system
  • Tissue-specific hierarchy of SESN2 effector pathways not systematically determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-9612973 Autophagy 5 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
KEAP1LKB1OTUB1PRKNRBX1SCAPSQSTM1ULK1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SESN2 (Hi95) is a stress-responsive gene induced by prolonged hypoxia, DNA damage (gamma/UV irradiation, doxorubicin), and oxidative stress; DNA damage induction is p53-dependent while hypoxia/oxidative stress induction is p53-independent. Overexpression causes apoptosis or sensitization to stress, but conditional overexpression can protect against hypoxia/glucose deprivation or H2O2. cDNA microarray, conditional overexpression in MCF7-tet-off cells, reporter assays Oncogene High 12203114
2016 SESN2 suppresses prolonged NLRP3 inflammasome activation by inducing mitophagy in macrophages via two mechanisms: (1) facilitating perinuclear mitochondrial clustering by mediating SQSTM1 (p62) aggregation and binding to Lys63-linked ubiquitins on mitochondria ('mitochondrial priming'), and (2) increasing ULK1 protein levels to activate autophagic machinery for primed mitochondria degradation. SESN2 expression is induced by NOS2-mediated NO upon extended LPS stimulation. Sesn2 knockout mice (two sepsis models), macrophage co-immunoprecipitation, immunofluorescence, Western blot, NLRP3 inflammasome activation assays Autophagy High 27337507
2016 SESN2 expression in melanocytes is induced by UVB via p53 and AKT3 pathways, and by UVA via mitochondria but not Nrf2. SESN2 negatively regulates UVB-induced DNA damage repair. SESN2 ablation increases UVA-induced Nrf2 induction and inhibits UVA-induced ROS production, placing SESN2 upstream of Nrf2 in the UVA response. SESN2 ablation (siRNA/KO), ROS measurement, Nrf2 induction assay, pathway inhibitor experiments in melanocytes Photochemistry and photobiology Medium 27463837
2016 ISO-mediated autophagy induction in bladder cancer cells occurs in a SESN2-dependent manner. ISO treatment induces SESN2 expression via MAPK8/JNK1-JUN-dependent AP-1 binding to the SESN2 promoter, with JUN binding to a consensus AP-1 site identified in the SESN2 promoter region. ChIP assay, luciferase reporter assay, siRNA knockdown, MAPK8 inhibitors, anchorage-independent growth assay Autophagy High 27171279
2017 LSD1/KDM1A binds to the promoter region of SESN2 and represses its transcription; pharmacological or genetic LSD1 inhibition triggers SESN2 expression, which inhibits mTORC1 activity and enhances autophagy in neuroblastoma cells. SESN2 overexpression is sufficient to promote autophagy, and SESN2 loss blunts LSD1 inhibition-induced autophagy. ChIP, LSD1 inhibitors (TCP, SP2509), LSD1 shRNA knockdown, SESN2 overexpression/knockdown, mTORC1 activity assays Oncogene High 28783174
2017 Sesn2 gene ablation in mice increases susceptibility to gentamicin-induced cochlear hair cell death; mechanistically, Sestrin-2 modulates AMPK/mTOR signaling—gentamicin downregulates AMPKα phosphorylation and upregulates p70S6K in wild-type but not Sesn2 knockout cochlear explants. Sesn2 knockout mice, gentamicin-treated cochlear explants, Western blot for AMPK/p70S6K, rapamycin treatment Cell death discovery Medium 28580173
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 cytosolic interaction. SESN2 downregulation inhibits Beclin1-Parkin interaction and prevents optimal mitochondrial Parkin accumulation. Mitochondrial superoxide triggers SESN2 activation; the Beclin1-Parkin cytosolic interaction is PINK1-independent but mitochondrial Parkin translocation is PINK1-dependent. Co-immunoprecipitation, SESN2 siRNA, ULK1 interaction assays, mitochondrial superoxide scavenging, PINK1 epistasis experiments Scientific reports High 29330382
2018 RBX1 (Ring box protein 1) is a novel E3 ubiquitin ligase that interacts with SESN2 and mediates its K48-linked polyubiquitination upon prolonged mitochondrial damage (CCCP treatment), leading to SESN2 degradation and cell death. RBX1 knockdown stabilizes SESN2 and reduces cell death. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), RBX1 siRNA knockdown, SESN2 overexpression rescue Molecular and cellular biochemistry Medium 29294217
2018 BDNF elevates neuronal ATF4 protein levels via TrkB signaling (independent of eIF2α phosphorylation), and ATF4 in turn mediates BDNF-promoted transcriptional induction of SESN2. ATF4 knockdown blocks BDNF-induced SESN2 upregulation, placing ATF4 upstream of SESN2 in the BDNF neuroprotective signaling pathway. Transcriptome analysis, ATF4 knockdown, TrkB inhibitors, Western blot, neuron culture Frontiers in molecular neuroscience Medium 29599707
2019 SESN2 interacts with Parkin and p62, promotes accumulation of Parkin to mitochondria, and alleviates doxorubicin-caused inhibition of Parkin-mediated mitophagy. SESN2 knockout (via sgRNA) inhibits Parkin-mediated mitophagy and causes mitochondrial dysfunction and cardiomyocyte apoptosis, while SESN2 overexpression protects against doxorubicin-induced cardiotoxicity. sgRNA SESN2 knockout, SESN2 overexpression, co-immunoprecipitation (SESN2-Parkin, SESN2-p62), mitophagy assays, echocardiography Journal of molecular and cellular cardiology High 31199952
2019 DHA enhances oxaliplatin-induced autophagic cell death via ER stress/SESN2 pathway. CHOP (ER stress transcription factor) binds the SESN2 promoter and increases SESN2 expression upon oxaliplatin+DHA treatment, and SESN2 is required for the enhanced autophagic response. ChIP (CHOP binding to SESN2 promoter), SESN2 siRNA, Western blot, in vitro/in vivo CRC models Cancers Medium 31337142
2020 SESN2 is localized on mitochondria, as demonstrated by direct mitochondrial fractionation experiments. This mitochondrial localization may underlie mTORC1-independent regulation of mitochondrial functions by SESN2. Mitochondrial fractionation, subcellular localization assays, live-cell imaging PloS one Medium 32287270
2020 JMJD3 (histone demethylase) negatively regulates SESN2 transcription by reducing H3K27me3 enrichment at the SESN2 promoter region. JMJD3 inhibition or knockdown preserves SESN2 expression and protects against doxorubicin-induced cardiomyopathy; JMJD3 overexpression aggravates cardiotoxicity, reversed by SESN2 overexpression. ChIP (H3K27me3 at SESN2 promoter), JMJD3 KD/OE, SESN2 OE rescue, Western blot, cardiac function assays Frontiers in cell and developmental biology Medium 33117796
2021 SESN2 is induced by the ER stress-activated transcription factor C/EBPβ. Once induced, SESN2 inhibits mTORC1 to attenuate ER stress and activates ULK1-mediated autophagic machinery, facilitating SQSTM1/p62 aggregation on mitochondrial surfaces to promote mitophagy. SESN2 knockdown aggravates denervation-induced muscle atrophy. SESN2 siRNA knockdown, C2C12 cells + rotenone, mouse denervation model, co-immunoprecipitation, Western blot for mTORC1, mitophagy assays Cell death & disease Medium 34429398
2021 SESN2 promotes NRF2 protein expression by enhancing p62-dependent autophagy in endothelial progenitor cells treated with Angiotensin II. SESN2 overexpression attenuates Ang-II-induced apoptosis; NRF2 silencing reverses SESN2-mediated protection, placing SESN2 upstream of NRF2 via p62/autophagy. SESN2 overexpression, NRF2 siRNA knockdown, p62-autophagy pathway analysis, Western blot, Transwell assays Aging Medium 33231566
2021 SESN2 activates PERK downstream signaling and directly regulates NRF2 signaling during ER stress in porcine oocytes. SESN2 siRNA knockdown interrupts NRF2 nuclear activation and spindle assembly. NRF2 inhibition does not affect SESN2 protein levels, placing SESN2 upstream of NRF2 in the PERK/SESN2/NRF2 axis. SESN2 siRNA knockdown in porcine oocytes, NRF2 inhibitor (ochratoxin A), Western blot, immunofluorescence Free radical biology & medicine Medium 34923100
2022 SESN2 promotes formation of complexes between AMPK and LKB1, thereby facilitating LKB1-mediated AMPK-T172 phosphorylation in skeletal muscle. In SESN2-/- mice, LKB1 expression increases with globular adiponectin treatment but pAMPK-T172 remains unchanged, demonstrating SESN2 is required for LKB1 to phosphorylate AMPK. Co-immunoprecipitation confirmed SESN2-promoted AMPK-LKB1 complex formation. SESN2-/- mice, immunoprecipitation of AMPK-LKB1 complex, SESN2 OE/inhibition in C2C12 myotubes, in vivo insulin signaling assays Sports medicine and health science Medium 36994173
2023 UPRmt upregulates SESN2 through the Eif2ak4/eIF2α/Atf4 pathway. SESN2 then promotes mitophagy by facilitating translocation of cytosolic Parkin and SQSTM1 to defective mitochondria, with SQSTM1 translocation dependent on Parkin. Two functional domains of SESN2 are necessary for interaction with Parkin and SQSTM1. Cytosolic Parkin-SQSTM1 interaction via SESN2 is PINK1-independent but mitochondrial translocation requires PINK1. SESN2 siRNA, Sesn2-/- mice (IVDD model), domain deletion mutagenesis, co-immunoprecipitation, mitophagy assays, in vivo disc degeneration assessment International journal of biological sciences High 36632468
2023 SESN2 inhibits SREBP1 transcriptional activity for lipogenesis by interacting with SCAP (SREBP cleavage-activating protein), thereby deactivating SREBP1-mediated lipogenic enzyme expression in chondrocytes. SESN2 overexpression via AAV in DMM OA mice ameliorates cartilage degeneration by inhibiting fatty acid synthesis. Co-immunoprecipitation (SESN2-SCAP interaction), SESN2 KD/OE, AAV-mediated overexpression in DMM mouse model, Western blot for lipogenic enzymes iScience Medium 40822351
2023 SESN2 inhibits STAT3 activation by maintaining expression of the PTPRD phosphatase, which dephosphorylates STAT3. SESN1&2 inactivation in A549 lung adenocarcinoma cells stimulates STAT3 by downregulating PTPRD, promoting cell proliferation and drug resistance through mTORC1-independent mechanisms. SESN1/2 double KO in A549 cells, STAT3 phosphorylation measurement, PTPRD expression analysis, cell proliferation and death assays Cell communication and signaling Medium 39985075
2023 miR-182-5p directly targets the 3'-UTR of SESN2 mRNA; miR-182-5p overexpression suppresses SESN2 expression and enhances radiation-induced ROS and cytotoxicity. ATO suppresses miR-182-5p to upregulate SESN2 via AGO2-dependent gene silencing; ribonucleoprotein immunoprecipitation confirmed ATO-induced stabilization of SESN2 mRNA. Luciferase reporter assay (SESN2 3'-UTR), miR-182-5p mimic transfection, RNP-IP (AGO2), Western blot, ROS measurement Oncotarget Medium 29662624
2023 Melatonin enhances the SESN2-SHP (small heterodimer partner) signaling cascade to suppress CREBH-mediated hepatic gluconeogenic gene transcription. SESN2-SHP compete with BTG2 for CREBH interaction, blocking CRBN-BTG2-CREBH axis-driven gluconeogenesis. SESN2 and SHP silencing reverses melatonin's protective effects. Sesn2/Shp silencing in primary hepatocytes and diabetic mice, gene expression analysis, competition binding assay for CREBH interaction Experimental & molecular medicine Medium 37488285
2024 SETDB1 histone methyltransferase collaborates with HP1β to label H3K9me3 on the SESN2 promoter, thereby repressing SESN2 expression. SETDB1 inhibition or knockdown de-represses SESN2 and reduces mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury. Chromatin immunoprecipitation and co-immunoprecipitation confirmed SETDB1/HP1β-H3K9me3-SESN2 promoter mechanism. ChIP (H3K9me3 at SESN2 promoter), CoIP (SETDB1-HP1β), SETDB1 inhibitor (R,R)-59, knockdown viruses, in vivo renal I/R mouse model BMC biology High 39443993
2024 FTO (m6A demethylase) destabilizes SESN2 mRNA by reducing m6A modification; FTO knockdown increases m6A levels at exon 9 of SESN2 and promotes binding of IGF2BP1 to SESN2 mRNA, enhancing SESN2 mRNA stability and protein expression. SESN2 upregulation activates AMPK-mTOR signaling to induce autophagic flux and suppress NSCLC growth. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A measurement, IGF2BP1 RIP, SESN2 mRNA stability assay, FTO KD, Western blot for AMPK/mTOR pathway Heliyon Medium 38495179
2024 LSD1 regulates SESN2 expression by modulating H3K4me1/2 enrichment at the SESN2 promoter region; LSD1 overexpression increases H3K4me1/2 at the SESN2 promoter and increases SESN2 expression, promoting autophagy via the SESN2/AMPK/ULK1 pathway to activate hepatic stellate cells. ChIP (H3K4me1/2 at SESN2 promoter), LSD1 OE and SESN2 silencing, autophagy inhibitors (3-MA, chloroquine), Western blot Environmental toxicology Medium 38477077
2025 KSHV-encoded vCyclin (a Cyclin D homolog) directly interacts with SESN2 and promotes its stabilization by recruiting the deubiquitinase OTUB1, thereby blocking SESN2 polyubiquitination and proteasomal degradation. vCyclin-OTUB1-stabilized SESN2 activates AMPK to support primary effusion lymphoma cell survival. Lysine at residue 74 of vCyclin is required for cytosolic localization, OTUB1 recruitment, and SESN2 stabilization. Co-immunoprecipitation (vCyclin-SESN2-OTUB1), site-directed mutagenesis (vCyclin K74), ubiquitination assay, SESN2 OE/KD, AMPK activity measurement Proceedings of the National Academy of Sciences of the United States of America High 41196342
2024 SESN2 inhibits ferroptosis in ischemia-reperfusion injured brain microvascular endothelial cells by promoting expression of System Xc- and GPX4. SESN2 silencing reduces System Xc- and GPX4 expression, while SESN2 overexpression promotes their expression, negatively regulating ferroptosis via the System Xc-/GPX4 pathway. SESN2 siRNA/OE in bEND.3 cells, OGD/R model, ferroptosis markers measurement, GPX4/System Xc- protein expression, bioinformatics + experimental validation Frontiers in genetics Medium 39944356
2025 LncRNA ZFAS1 functions as a ceRNA for miR-138-5p to upregulate SESN2 expression; miR-138-5p directly and negatively regulates SESN2. This ZFAS1/miR-138-5p/SESN2 axis controls sepsis-induced cardiomyocyte pyroptosis. Validated by dual-luciferase reporter and RNA pull-down assays. Dual-luciferase reporter assay, RNA pull-down assay, ZFAS1/SESN2 OE and KD in H9C2 cells and LPS-treated rats Immunology letters Medium 34271014
2025 Galangin activates NRF2 nuclear translocation by promoting KEAP1/SESN2 formation and KEAP1/NRF2 dissociation, thereby suppressing ferroptosis. Co-immunoprecipitation confirmed SESN2-KEAP1 interaction. SESN2 siRNA abolishes the protective effect of galangin. Co-immunoprecipitation (SESN2-KEAP1), SESN2 siRNA, NRF2 inhibitor ML385, molecular docking, in vivo mouse model and Caco-2 cells Journal of agricultural and food chemistry Medium 41605867

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 317 12203114
2016 SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy 238 27337507
2019 SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function. Journal of molecular and cellular cardiology 89 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 81 34601081
2020 Hexavalent chromium induced heart dysfunction via Sesn2-mediated impairment of mitochondrial function and energy supply. Chemosphere 72 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 64 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 57 37298433
2018 SESN2 facilitates mitophagy by helping Parkin translocation through ULK1 mediated Beclin1 phosphorylation. Scientific reports 55 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 47 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 41 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
2017 Mesoporous Carbon@Titanium Nitride Hollow Spheres as an Efficient SeS2 Host for Advanced Li-SeS2 Batteries. Angewandte Chemie (International ed. in English) 39 29072802
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
2019 Encapsulation of SeS2 into Nitrogen-Doped Free-Standing Carbon Nanofiber Film Enabling Long Cycle Life and High Energy Density K-SeS2 Battery. ACS nano 36 30946566
2017 Sesn2 gene ablation enhances susceptibility to gentamicin-induced hair cell death via modulation of AMPK/mTOR signaling. Cell death discovery 36 28580173
2021 SESN2 protects against denervated muscle atrophy through unfolded protein response and mitophagy. Cell death & disease 33 34429398
2021 Molecular pathways in sepsis-induced cardiomyocyte pyroptosis: Novel finding on long non-coding RNA ZFAS1/miR-138-5p/SESN2 axis. Immunology letters 32 34271014
2020 Sulforaphane attenuates hexavalent chromium-induced cardiotoxicity via the activation of the Sesn2/AMPK/Nrf2 signaling pathway. Metallomics : integrated biometal science 32 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 31 34923100
2020 Mitochondrial localization of SESN2. PloS one 28 32287270
2020 Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression. Frontiers in cell and developmental biology 27 33117796
2016 Oleanolic acid attenuates liver ischemia reperfusion injury by HO-1/Sesn2 signaling pathway. Hepatobiliary & pancreatic diseases international : HBPD INT 24 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 Sesn2 Serves as a Regulator between Mitochondrial Unfolded Protein Response and Mitophagy in Intervertebral Disc Degeneration. International journal of biological sciences 23 36632468
2022 Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling. The Journal of nutritional biochemistry 20 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 20 34688462
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 19 37788754
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
2024 Tangeretin alleviates inflammation and oxidative response induced by spinal cord injury by activating the Sesn2/Keap1/Nrf2 pathway. Phytotherapy research : PTR 17 39054118
2022 SESN2 prevents the slow-to-fast myofiber shift in denervated atrophy via AMPK/PGC-1α pathway. Cellular & molecular biology letters 16 35945510
2020 Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway. Aging 16 33231566
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
2018 Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) in Neurons and Promotes ATF4-Dependent Induction of Sesn2. Frontiers in molecular neuroscience 15 29599707
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 11 38432454
2022 Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity. Cells 11 36010689
2019 Genetic association of DDIT3, RPL23A, SESN2 and NR4A1 genes with milk yield and composition in dairy cattle. Animal genetics 11 30815908
2025 p53-regulated SESN1 and SESN2 regulate cell proliferation and cell death through control of STAT3. Cell communication and signaling : CCS 9 39985075
2024 N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells. Inflammation 9 39037665
2023 Solanine Represses Gastric Cancer Growth by Mediating Autophagy Through AAMDC/MYC/ATF4/Sesn2 Signaling Pathway. Drug design, development and therapy 9 36789094
2022 Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2. Sports medicine and health science 9 36994173
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 9 34038646
2024 Understanding the electrochemical processes of SeS2 positive electrodes for developing high-performance non-aqueous lithium sulfur batteries. Nature communications 8 39227369
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
2023 Circular RNA SESN2 aggravates gestational trophoblast cell damage induced by high glucose by binding to IGF2BP2. Molecular reproduction and development 7 36623264
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 Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway. Experimental & molecular medicine 7 37488285
2023 Gallic acid as a Sestrin (SESN2) activator and potential obesity therapeutic agent: A molecular docking study. Gene 7 37536400
2023 Melatonin Ameliorates Ovarian Hyperstimulation Syndrome (OHSS) through SESN2 Regulated Antiapoptosis. Obstetrics and gynecology international 7 37937274
2025 Cyanidin-3-O-glucoside mitigates Staphylococcus aureus-induced mastitis by suppressing inflammatory responses and Ferroptosis mediated by SESN2/Nrf2. International immunopharmacology 6 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 6 38788813
2023 Sestrin2 protects against hypoxic nerve injury by regulating mitophagy through SESN2/AMPK pathway. Frontiers in molecular biosciences 6 37808523
2022 SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells. Cells 6 36611970
2024 FTO-mediated autophagy inhibition promotes non-small cell lung cancer progression by reducing the stability of SESN2 mRNA. Heliyon 5 38495179
2022 Clinical application of RUBCN/SESN2 mediated inhibition of autophagy as biomarkers of diabetic kidney disease. Molecular medicine (Cambridge, Mass.) 5 36476132
2025 MK8722 alleviates osteoarthritis by activating Sesn2 and transcriptionally upregulating BNIP3 to promote mitophagy and inhibit chondrocyte ferroptosis. Journal of advanced research 4 41077348
2024 Mir-615-3p promotes osteosarcoma progression via the SESN2/AMPK/mTOR pathway. Cancer cell international 4 39702297
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 Exercise-induced Sesn2 mediates autophagic flux to alleviate neural damage after ischemic stroke in mice. Experimental neurology 3 39904418
2025 Knockdown of SESN2 Exacerbates Cerebral Ischemia-Reperfusion Injury Through Enhancing Glycolysis via the mTOR/HIF-1α Pathway. CNS neuroscience & therapeutics 3 40032632
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 Inhibition of Sesn2 has negative regulatory effects on the myogenic differentiation of C2C12 myoblasts. Molecular biomedicine 3 39117956
2024 Shionone Inhibits Glomerular Fibirosis by Suppressing NLRP3 Related Inflammasome though SESN2-NRF2/ HO-1 Pathway. Diabetes & metabolism journal 3 39192821
2024 The C/EBPβ-SESN2 Axis Promotes M2b Macrophage Polarization Induced by T.cp-MIF to Suppress Inflammation in Thelazia Callipaeda Infection. Inflammation 3 39215929
2023 Resveratrol Promotes Gluconeogenesis by Inhibiting SESN2-mTORC2-AKT Pathway in Calf Hepatocytes. The Journal of nutrition 3 37182694
2023 SESN2 attenuates sevoflurane-induced cognitive impairment and neuroinflammation in rats. Experimental brain research 3 38129329
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
2025 Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc-/GPX4 pathway. Frontiers in genetics 2 39944356
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 CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice. Journal of cachexia, sarcopenia and muscle 2 41030226
2024 Hyperglycemia exacerbates cerebral ischemia/reperfusion injury by up-regulating autophagy through p53-Sesn2-AMPK pathway. Neuroscience letters 2 38191089
2024 DNA methylation-driven gene FAM3D promotes colorectal cancer growth via the ATF4-SESN2-mTORC1 pathway. Aging 2 39388305
2023 Farnesoid X Receptor (FXR) Regulates mTORC1 Signaling and Autophagy by Inhibiting SESN2 Expression. Molecular nutrition & food research 2 36715418
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 Lightly Se-Doped Monolayer MoS2 Grown by Chemical Vapor Deposition Using SeS2 Precursor. ACS applied materials & interfaces 1 40228164
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 1 40601221
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 Lactoferrin-cyanidin-3-glucoside nanoparticles alleviate inflammation and oxidative stress via Sesn2/Nrf2 activation in mastitis. Materials today. Bio 1 41281654
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
2024 SETDB1 targeting SESN2 regulates mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury. BMC biology 1 39443993
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 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 0 41605867
2026 [Protective effects of SESN2 on Erastin-induced ferroptosis in renal tubular cells and acute kidney injury]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 42032961
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 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 0 40485171
2025 SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway. International journal of biological sciences 0 40612680
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
2024 SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy. Cell biochemistry and biophysics 0 39417977