{"gene":"SESN2","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"cDNA microarray, conditional overexpression in MCF7-tet-off cells, reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — original discovery, multiple orthogonal methods, replicated across stress conditions","pmids":["12203114"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Sesn2 knockout mice (two sepsis models), macrophage co-immunoprecipitation, immunofluorescence, Western blot, NLRP3 inflammasome activation assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined phenotype, reciprocal co-IP, multiple orthogonal methods","pmids":["27337507"],"is_preprint":false},{"year":2016,"finding":"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.","method":"SESN2 ablation (siRNA/KO), ROS measurement, Nrf2 induction assay, pathway inhibitor experiments in melanocytes","journal":"Photochemistry and photobiology","confidence":"Medium","confidence_rationale":"Tier 2 — KD/KO with defined mechanistic phenotype, single lab","pmids":["27463837"],"is_preprint":false},{"year":2016,"finding":"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.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, MAPK8 inhibitors, anchorage-independent growth assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP, luciferase reporter, and KD with orthogonal functional readouts","pmids":["27171279"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP, LSD1 inhibitors (TCP, SP2509), LSD1 shRNA knockdown, SESN2 overexpression/knockdown, mTORC1 activity assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP confirming promoter binding, multiple orthogonal approaches, epistasis established","pmids":["28783174"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Sesn2 knockout mice, gentamicin-treated cochlear explants, Western blot for AMPK/p70S6K, rapamycin treatment","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype and pathway verification","pmids":["28580173"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, SESN2 siRNA, ULK1 interaction assays, mitochondrial superoxide scavenging, PINK1 epistasis experiments","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, epistasis with PINK1, multiple mechanistic validations in single study","pmids":["29330382"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), RBX1 siRNA knockdown, SESN2 overexpression rescue","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP identifying E3 ligase, linkage-specific ubiquitination assay, single lab","pmids":["29294217"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Transcriptome analysis, ATF4 knockdown, TrkB inhibitors, Western blot, neuron culture","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomics plus mechanistic KD validation, single lab","pmids":["29599707"],"is_preprint":false},{"year":2019,"finding":"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.","method":"sgRNA SESN2 knockout, SESN2 overexpression, co-immunoprecipitation (SESN2-Parkin, SESN2-p62), mitophagy assays, echocardiography","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 — KO and OE with defined cardiac phenotype, reciprocal co-IP with two partners","pmids":["31199952"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP (CHOP binding to SESN2 promoter), SESN2 siRNA, Western blot, in vitro/in vivo CRC models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirming promoter binding, SESN2 KD epistasis, single lab","pmids":["31337142"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Mitochondrial fractionation, subcellular localization assays, live-cell imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation experiment demonstrating localization, single lab","pmids":["32287270"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ChIP (H3K27me3 at SESN2 promoter), JMJD3 KD/OE, SESN2 OE rescue, Western blot, cardiac function assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for epigenetic mark, epistasis via rescue experiment, single lab","pmids":["33117796"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SESN2 siRNA knockdown, C2C12 cells + rotenone, mouse denervation model, co-immunoprecipitation, Western blot for mTORC1, mitophagy assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined phenotype, C/EBPβ induction mechanism, pathway epistasis, single lab","pmids":["34429398"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SESN2 overexpression, NRF2 siRNA knockdown, p62-autophagy pathway analysis, Western blot, Transwell assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic epistasis (SESN2→p62→NRF2) established by OE and KD, single lab","pmids":["33231566"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SESN2 siRNA knockdown in porcine oocytes, NRF2 inhibitor (ochratoxin A), Western blot, immunofluorescence","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA with functional oocyte maturation readout, epistasis established, single lab","pmids":["34923100"],"is_preprint":false},{"year":2022,"finding":"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.","method":"SESN2-/- mice, immunoprecipitation of AMPK-LKB1 complex, SESN2 OE/inhibition in C2C12 myotubes, in vivo insulin signaling assays","journal":"Sports medicine and health science","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP demonstrating SESN2-facilitated AMPK-LKB1 complex, KO mouse epistasis, single lab","pmids":["36994173"],"is_preprint":false},{"year":2023,"finding":"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.","method":"SESN2 siRNA, Sesn2-/- mice (IVDD model), domain deletion mutagenesis, co-immunoprecipitation, mitophagy assays, in vivo disc degeneration assessment","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis, co-IP, KO mouse, epistasis with PINK1, replicated mechanistic chain","pmids":["36632468"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation (SESN2-SCAP interaction), SESN2 KD/OE, AAV-mediated overexpression in DMM mouse model, Western blot for lipogenic enzymes","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP establishing novel SESN2-SCAP interaction, in vivo AAV model, single lab","pmids":["40822351"],"is_preprint":false},{"year":2023,"finding":"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.","method":"SESN1/2 double KO in A549 cells, STAT3 phosphorylation measurement, PTPRD expression analysis, cell proliferation and death assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined pathway mechanism (SESN2→PTPRD→STAT3), single lab","pmids":["39985075"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Luciferase reporter assay (SESN2 3'-UTR), miR-182-5p mimic transfection, RNP-IP (AGO2), Western blot, ROS measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter validating direct miRNA-target interaction, RNP-IP confirming AGO2-mediated regulation","pmids":["29662624"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Sesn2/Shp silencing in primary hepatocytes and diabetic mice, gene expression analysis, competition binding assay for CREBH interaction","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KD epistasis in vivo and in vitro, competitive interaction with CREBH mechanistically defined, single lab","pmids":["37488285"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP (H3K9me3 at SESN2 promoter), CoIP (SETDB1-HP1β), SETDB1 inhibitor (R,R)-59, knockdown viruses, in vivo renal I/R mouse model","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP and CoIP mechanistically defining epigenetic repression, in vivo model with defined phenotype","pmids":["39443993"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A measurement, IGF2BP1 RIP, SESN2 mRNA stability assay, FTO KD, Western blot for AMPK/mTOR pathway","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP-seq identifying m6A site, RIP confirming reader protein binding, mRNA stability assay, single lab","pmids":["38495179"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP (H3K4me1/2 at SESN2 promoter), LSD1 OE and SESN2 silencing, autophagy inhibitors (3-MA, chloroquine), Western blot","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for histone marks at SESN2 promoter, epistasis by SESN2 silencing, single lab","pmids":["38477077"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation (vCyclin-SESN2-OTUB1), site-directed mutagenesis (vCyclin K74), ubiquitination assay, SESN2 OE/KD, AMPK activity measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP with mutagenesis, ubiquitination assay, deubiquitinase identification, functional validation in lymphoma cells","pmids":["41196342"],"is_preprint":false},{"year":2024,"finding":"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.","method":"SESN2 siRNA/OE in bEND.3 cells, OGD/R model, ferroptosis markers measurement, GPX4/System Xc- protein expression, bioinformatics + experimental validation","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss of function with defined ferroptosis pathway placement, single lab","pmids":["39944356"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Dual-luciferase reporter assay, RNA pull-down assay, ZFAS1/SESN2 OE and KD in H9C2 cells and LPS-treated rats","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter and RNA pulldown validating ceRNA mechanism, functional epistasis","pmids":["34271014"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation (SESN2-KEAP1), SESN2 siRNA, NRF2 inhibitor ML385, molecular docking, in vivo mouse model and Caco-2 cells","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP confirming SESN2-KEAP1 physical interaction, siRNA epistasis, single lab","pmids":["41605867"],"is_preprint":false}],"current_model":"SESN2 is a stress-inducible protein transcriptionally activated by p53 (DNA damage), ATF4/C/EBPβ (ER/metabolic stress), AP-1/JNK (oxidative stress), and BDNF/TrkB (neuroprotection), and epigenetically repressed by LSD1, JMJD3, and SETDB1/HP1β via histone modifications at its promoter; once induced, SESN2 inhibits mTORC1 by binding GATOR2, promotes mitophagy by facilitating ULK1-mediated Beclin1-S14 phosphorylation and Parkin/SQSTM1 translocation to mitochondria (PINK1-dependent step), activates AMPK by promoting LKB1-AMPK complex formation, suppresses STAT3 via PTPRD phosphatase, interacts with KEAP1 to promote NRF2 nuclear translocation, inhibits lipogenesis by binding SCAP to block SREBP1, and is itself regulated post-translationally by RBX1-mediated K48-linked ubiquitination (degradation) or vCyclin-OTUB1-mediated deubiquitination (stabilization)."},"narrative":{"teleology":[{"year":2002,"claim":"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","pmids":["12203114"],"confidence":"High","gaps":["Downstream effector mechanism unknown at this stage","No interacting partners identified","p53-independent induction pathway not molecularly defined"]},{"year":2016,"claim":"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","pmids":["27337507"],"confidence":"High","gaps":["Direct SESN2–ULK1 binding interface not mapped","Relative contribution of SQSTM1 aggregation versus ULK1 stabilization not quantified"]},{"year":2016,"claim":"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","pmids":["27171279"],"confidence":"High","gaps":["Whether AP-1 cooperates with or substitutes for p53 at the SESN2 promoter not determined","Other AP-1 family members not tested"]},{"year":2017,"claim":"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","pmids":["28783174"],"confidence":"High","gaps":["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"]},{"year":2018,"claim":"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","pmids":["29330382"],"confidence":"High","gaps":["Whether SESN2 directly bridges ULK1 and Beclin1 or acts allosterically not resolved","Structural basis of SESN2–ULK1 interaction unknown"]},{"year":2018,"claim":"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","pmids":["29294217"],"confidence":"Medium","gaps":["Specific lysine residues on SESN2 targeted by RBX1 not identified","CRL complex composition (Cullin partner, substrate adaptor) not defined","Not independently replicated"]},{"year":2018,"claim":"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","pmids":["29599707"],"confidence":"Medium","gaps":["Whether ATF4 binds directly to the SESN2 promoter in this context not shown by ChIP","Functional neuroprotective readout downstream of SESN2 not fully defined"]},{"year":2019,"claim":"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","pmids":["31199952"],"confidence":"High","gaps":["Whether SESN2 forms a ternary complex with Parkin and p62 simultaneously versus sequential interactions not resolved"]},{"year":2020,"claim":"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","pmids":["32287270"],"confidence":"Medium","gaps":["Mechanism of mitochondrial targeting (signal sequence or protein interaction) not identified","Whether localization is constitutive or stress-dependent not fully resolved"]},{"year":2020,"claim":"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","pmids":["33117796","39443993"],"confidence":"High","gaps":["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"]},{"year":2022,"claim":"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","pmids":["36994173"],"confidence":"Medium","gaps":["Whether SESN2 acts as a direct scaffold bridging LKB1 and AMPK or alters their conformations not determined","Single-lab finding awaits independent replication"]},{"year":2023,"claim":"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","pmids":["36632468"],"confidence":"High","gaps":["Structural resolution of SESN2 domains binding Parkin and p62 lacking","Whether these domains function independently or cooperatively not determined"]},{"year":2023,"claim":"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","pmids":["40822351"],"confidence":"Medium","gaps":["Whether SESN2–SCAP interaction is direct or mediated by a complex not established","Binding domain on SESN2 for SCAP not mapped"]},{"year":2023,"claim":"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","pmids":["39985075"],"confidence":"Medium","gaps":["Mechanism by which SESN2 maintains PTPRD expression not defined","Whether SESN2 directly regulates PTPRD transcription or protein stability unknown"]},{"year":2024,"claim":"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","pmids":["38495179"],"confidence":"Medium","gaps":["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"]},{"year":2025,"claim":"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","pmids":["41196342"],"confidence":"High","gaps":["Whether OTUB1 regulates endogenous SESN2 turnover in the absence of vCyclin not tested","Relationship between OTUB1 and RBX1-mediated degradation not examined"]},{"year":2025,"claim":"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","pmids":["41605867"],"confidence":"Medium","gaps":["Whether SESN2 competes with NRF2 for the same KEAP1 binding site not structurally resolved","Stoichiometry of SESN2–KEAP1 interaction not determined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,16,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,19,28]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,3,4,6,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,16,19]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,10,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[18,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[26,28]}],"complexes":[],"partners":["PRKN","SQSTM1","ULK1","KEAP1","SCAP","RBX1","LKB1","OTUB1"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P58004","full_name":"Sestrin-2","aliases":["Hypoxia-induced gene"],"length_aa":480,"mass_kda":54.5,"function":"Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26586190, PubMed:26612684, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26586190, PubMed:26612684, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190, PubMed:35114100, PubMed:35831510, PubMed:36528027). 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 mTORC1 (PubMed:24947615). 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 (PubMed:23274085). May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468). Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P58004/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SESN2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SESN2","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"607767","title":"SESTRIN 2; SESN2","url":"https://www.omim.org/entry/607767"},{"mim_id":"606103","title":"SESTRIN 1; SESN1","url":"https://www.omim.org/entry/606103"},{"mim_id":"188400","title":"DIGEORGE SYNDROME; DGS","url":"https://www.omim.org/entry/188400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SESN2"},"hgnc":{"alias_symbol":["SES2","DKFZp761M0212","HI95","SEST2"],"prev_symbol":[]},"alphafold":{"accession":"P58004","domains":[{"cath_id":"1.20.1290.10","chopping":"43-213","consensus_level":"medium","plddt":89.9081,"start":43,"end":213},{"cath_id":"-","chopping":"254-302_318-462","consensus_level":"medium","plddt":91.6622,"start":254,"end":462}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58004","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58004-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58004-F1-predicted_aligned_error_v6.png","plddt_mean":81.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SESN2","jax_strain_url":"https://www.jax.org/strain/search?query=SESN2"},"sequence":{"accession":"P58004","fasta_url":"https://rest.uniprot.org/uniprotkb/P58004.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58004/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58004"}},"corpus_meta":[{"pmid":"12203114","id":"PMC_12203114","title":"Identification 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agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/38551359","citation_count":3,"is_preprint":false},{"pmid":"40775338","id":"PMC_40775338","title":"SREBF1-mediated SND1 transcriptional activation promotes prostate cancer progression via MTDH interaction through the SESN2/AMPK/mTOR axis.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40775338","citation_count":2,"is_preprint":false},{"pmid":"41030226","id":"PMC_41030226","title":"CSE/H2S/SESN2 Signalling Mediates the Protective Effect of Exercise Against Immobilization-Induced Muscle Atrophy in Mice.","date":"2025","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/41030226","citation_count":2,"is_preprint":false},{"pmid":"38191089","id":"PMC_38191089","title":"Hyperglycemia exacerbates cerebral ischemia/reperfusion injury by up-regulating autophagy through p53-Sesn2-AMPK pathway.","date":"2024","source":"Neuroscience 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pathway.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/39388305","citation_count":2,"is_preprint":false},{"pmid":"39944356","id":"PMC_39944356","title":"Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc-/GPX4 pathway.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39944356","citation_count":2,"is_preprint":false},{"pmid":"39443993","id":"PMC_39443993","title":"SETDB1 targeting SESN2 regulates mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury.","date":"2024","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/39443993","citation_count":1,"is_preprint":false},{"pmid":"40842769","id":"PMC_40842769","title":"Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40842769","citation_count":1,"is_preprint":false},{"pmid":"41351982","id":"PMC_41351982","title":"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.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41351982","citation_count":1,"is_preprint":false},{"pmid":"38477077","id":"PMC_38477077","title":"Lysine specific demethylase 1 inhibits sodium arsenite activation of HSCs by regulating SESN2/AMPK/ULK1 signaling pathway activity.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38477077","citation_count":1,"is_preprint":false},{"pmid":"41086475","id":"PMC_41086475","title":"Polylactic acid microplastics and fish species intestinal inflammation risk: Associated with mitochondrial function mediated by Sesn2/Nrf2 pathway.","date":"2025","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/41086475","citation_count":1,"is_preprint":false},{"pmid":"40822351","id":"PMC_40822351","title":"SESN2 maintains cartilage homeostasis by SREBP1-mediated lipid metabolism during osteoarthritis progression.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40822351","citation_count":1,"is_preprint":false},{"pmid":"41281654","id":"PMC_41281654","title":"Lactoferrin-cyanidin-3-glucoside nanoparticles alleviate inflammation and oxidative stress via Sesn2/Nrf2 activation in mastitis.","date":"2025","source":"Materials today. Bio","url":"https://pubmed.ncbi.nlm.nih.gov/41281654","citation_count":1,"is_preprint":false},{"pmid":"40601221","id":"PMC_40601221","title":"Serum Hsa-miR-4695-5p Serves as a Novel Diagnostic Biomarker for Acute Severe Pancreatitis and Exacerbates Pathological Injury by Targeting SESN2.","date":"2025","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40601221","citation_count":1,"is_preprint":false},{"pmid":"32511948","id":"PMC_32511948","title":"WITHDRAWN: GAS5 enhances natural killer cell-mediated killing by promoting ubiquitination of SESN2 in prostate cancer cells.","date":"2020","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32511948","citation_count":1,"is_preprint":false},{"pmid":"40228164","id":"PMC_40228164","title":"Lightly Se-Doped Monolayer MoS2 Grown by Chemical Vapor Deposition Using SeS2 Precursor.","date":"2025","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/40228164","citation_count":1,"is_preprint":false},{"pmid":"40485171","id":"PMC_40485171","title":"Direct scavenging of ROS by S-PPE NP reduces oxidative stress-induced stimulation of the SESN2/AMPK/KIM-1 pathway in acute kidney injury.","date":"2025","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/40485171","citation_count":0,"is_preprint":false},{"pmid":"40425138","id":"PMC_40425138","title":"SESN2 mediates resistance training-induced improvements in exercise performance and energy metabolism in C57BL/6J mice.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40425138","citation_count":0,"is_preprint":false},{"pmid":"40612680","id":"PMC_40612680","title":"SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40612680","citation_count":0,"is_preprint":false},{"pmid":"41196342","id":"PMC_41196342","title":"A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41196342","citation_count":0,"is_preprint":false},{"pmid":"39417977","id":"PMC_39417977","title":"SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39417977","citation_count":0,"is_preprint":false},{"pmid":"40374019","id":"PMC_40374019","title":"Zinc finger transcription factor ZNF384 mitigates LPS-induced ferroptosis and inflammation in lung epithelial cells by activating SESN2-mediated autophagy.","date":"2025","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/40374019","citation_count":0,"is_preprint":false},{"pmid":"41527177","id":"PMC_41527177","title":"Inhibitory effect of blestriarene C on triple-negative breast cancer: Inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis.","date":"2026","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41527177","citation_count":0,"is_preprint":false},{"pmid":"41370333","id":"PMC_41370333","title":"Protective Effect of SESN2 on Glutamate Neurotoxicity via Keap1-Nrf2 Pathway-Mediated Mitophagy.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41370333","citation_count":0,"is_preprint":false},{"pmid":"41605867","id":"PMC_41605867","title":"Galangin Mitigates Alcohol-Induced Intestinal Damage by Suppressing Ferroptosis via the SESN2/KEAP1/NRF2 Pathway in Mice and Caco-2 Cells.","date":"2026","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41605867","citation_count":0,"is_preprint":false},{"pmid":"42032961","id":"PMC_42032961","title":"[Protective effects of SESN2 on Erastin-induced ferroptosis in renal tubular cells and acute kidney injury].","date":"2026","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42032961","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55814,"output_tokens":7817,"usd":0.142348},"stage2":{"model":"claude-opus-4-6","input_tokens":11524,"output_tokens":4743,"usd":0.264292},"total_usd":0.40664,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA microarray, conditional overexpression in MCF7-tet-off cells, reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery, multiple orthogonal methods, replicated across stress conditions\",\n      \"pmids\": [\"12203114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Sesn2 knockout mice (two sepsis models), macrophage co-immunoprecipitation, immunofluorescence, Western blot, NLRP3 inflammasome activation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined phenotype, reciprocal co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"27337507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 ablation (siRNA/KO), ROS measurement, Nrf2 induction assay, pathway inhibitor experiments in melanocytes\",\n      \"journal\": \"Photochemistry and photobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/KO with defined mechanistic phenotype, single lab\",\n      \"pmids\": [\"27463837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, MAPK8 inhibitors, anchorage-independent growth assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, luciferase reporter, and KD with orthogonal functional readouts\",\n      \"pmids\": [\"27171279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, LSD1 inhibitors (TCP, SP2509), LSD1 shRNA knockdown, SESN2 overexpression/knockdown, mTORC1 activity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP confirming promoter binding, multiple orthogonal approaches, epistasis established\",\n      \"pmids\": [\"28783174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Sesn2 knockout mice, gentamicin-treated cochlear explants, Western blot for AMPK/p70S6K, rapamycin treatment\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype and pathway verification\",\n      \"pmids\": [\"28580173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, SESN2 siRNA, ULK1 interaction assays, mitochondrial superoxide scavenging, PINK1 epistasis experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, epistasis with PINK1, multiple mechanistic validations in single study\",\n      \"pmids\": [\"29330382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), RBX1 siRNA knockdown, SESN2 overexpression rescue\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifying E3 ligase, linkage-specific ubiquitination assay, single lab\",\n      \"pmids\": [\"29294217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptome analysis, ATF4 knockdown, TrkB inhibitors, Western blot, neuron culture\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomics plus mechanistic KD validation, single lab\",\n      \"pmids\": [\"29599707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"sgRNA SESN2 knockout, SESN2 overexpression, co-immunoprecipitation (SESN2-Parkin, SESN2-p62), mitophagy assays, echocardiography\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO and OE with defined cardiac phenotype, reciprocal co-IP with two partners\",\n      \"pmids\": [\"31199952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (CHOP binding to SESN2 promoter), SESN2 siRNA, Western blot, in vitro/in vivo CRC models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming promoter binding, SESN2 KD epistasis, single lab\",\n      \"pmids\": [\"31337142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Mitochondrial fractionation, subcellular localization assays, live-cell imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation experiment demonstrating localization, single lab\",\n      \"pmids\": [\"32287270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (H3K27me3 at SESN2 promoter), JMJD3 KD/OE, SESN2 OE rescue, Western blot, cardiac function assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for epigenetic mark, epistasis via rescue experiment, single lab\",\n      \"pmids\": [\"33117796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 siRNA knockdown, C2C12 cells + rotenone, mouse denervation model, co-immunoprecipitation, Western blot for mTORC1, mitophagy assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined phenotype, C/EBPβ induction mechanism, pathway epistasis, single lab\",\n      \"pmids\": [\"34429398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 overexpression, NRF2 siRNA knockdown, p62-autophagy pathway analysis, Western blot, Transwell assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic epistasis (SESN2→p62→NRF2) established by OE and KD, single lab\",\n      \"pmids\": [\"33231566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 siRNA knockdown in porcine oocytes, NRF2 inhibitor (ochratoxin A), Western blot, immunofluorescence\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with functional oocyte maturation readout, epistasis established, single lab\",\n      \"pmids\": [\"34923100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2-/- mice, immunoprecipitation of AMPK-LKB1 complex, SESN2 OE/inhibition in C2C12 myotubes, in vivo insulin signaling assays\",\n      \"journal\": \"Sports medicine and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP demonstrating SESN2-facilitated AMPK-LKB1 complex, KO mouse epistasis, single lab\",\n      \"pmids\": [\"36994173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 siRNA, Sesn2-/- mice (IVDD model), domain deletion mutagenesis, co-immunoprecipitation, mitophagy assays, in vivo disc degeneration assessment\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis, co-IP, KO mouse, epistasis with PINK1, replicated mechanistic chain\",\n      \"pmids\": [\"36632468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SESN2-SCAP interaction), SESN2 KD/OE, AAV-mediated overexpression in DMM mouse model, Western blot for lipogenic enzymes\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP establishing novel SESN2-SCAP interaction, in vivo AAV model, single lab\",\n      \"pmids\": [\"40822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"SESN1/2 double KO in A549 cells, STAT3 phosphorylation measurement, PTPRD expression analysis, cell proliferation and death assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined pathway mechanism (SESN2→PTPRD→STAT3), single lab\",\n      \"pmids\": [\"39985075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay (SESN2 3'-UTR), miR-182-5p mimic transfection, RNP-IP (AGO2), Western blot, ROS measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter validating direct miRNA-target interaction, RNP-IP confirming AGO2-mediated regulation\",\n      \"pmids\": [\"29662624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Sesn2/Shp silencing in primary hepatocytes and diabetic mice, gene expression analysis, competition binding assay for CREBH interaction\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD epistasis in vivo and in vitro, competitive interaction with CREBH mechanistically defined, single lab\",\n      \"pmids\": [\"37488285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (H3K9me3 at SESN2 promoter), CoIP (SETDB1-HP1β), SETDB1 inhibitor (R,R)-59, knockdown viruses, in vivo renal I/R mouse model\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and CoIP mechanistically defining epigenetic repression, in vivo model with defined phenotype\",\n      \"pmids\": [\"39443993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A measurement, IGF2BP1 RIP, SESN2 mRNA stability assay, FTO KD, Western blot for AMPK/mTOR pathway\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP-seq identifying m6A site, RIP confirming reader protein binding, mRNA stability assay, single lab\",\n      \"pmids\": [\"38495179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (H3K4me1/2 at SESN2 promoter), LSD1 OE and SESN2 silencing, autophagy inhibitors (3-MA, chloroquine), Western blot\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for histone marks at SESN2 promoter, epistasis by SESN2 silencing, single lab\",\n      \"pmids\": [\"38477077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (vCyclin-SESN2-OTUB1), site-directed mutagenesis (vCyclin K74), ubiquitination assay, SESN2 OE/KD, AMPK activity measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP with mutagenesis, ubiquitination assay, deubiquitinase identification, functional validation in lymphoma cells\",\n      \"pmids\": [\"41196342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"SESN2 siRNA/OE in bEND.3 cells, OGD/R model, ferroptosis markers measurement, GPX4/System Xc- protein expression, bioinformatics + experimental validation\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with defined ferroptosis pathway placement, single lab\",\n      \"pmids\": [\"39944356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA pull-down assay, ZFAS1/SESN2 OE and KD in H9C2 cells and LPS-treated rats\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter and RNA pulldown validating ceRNA mechanism, functional epistasis\",\n      \"pmids\": [\"34271014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SESN2-KEAP1), SESN2 siRNA, NRF2 inhibitor ML385, molecular docking, in vivo mouse model and Caco-2 cells\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP confirming SESN2-KEAP1 physical interaction, siRNA epistasis, single lab\",\n      \"pmids\": [\"41605867\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SESN2 is a stress-inducible protein transcriptionally activated by p53 (DNA damage), ATF4/C/EBPβ (ER/metabolic stress), AP-1/JNK (oxidative stress), and BDNF/TrkB (neuroprotection), and epigenetically repressed by LSD1, JMJD3, and SETDB1/HP1β via histone modifications at its promoter; once induced, SESN2 inhibits mTORC1 by binding GATOR2, promotes mitophagy by facilitating ULK1-mediated Beclin1-S14 phosphorylation and Parkin/SQSTM1 translocation to mitochondria (PINK1-dependent step), activates AMPK by promoting LKB1-AMPK complex formation, suppresses STAT3 via PTPRD phosphatase, interacts with KEAP1 to promote NRF2 nuclear translocation, inhibits lipogenesis by binding SCAP to block SREBP1, and is itself regulated post-translationally by RBX1-mediated K48-linked ubiquitination (degradation) or vCyclin-OTUB1-mediated deubiquitination (stabilization).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA microarray and conditional overexpression in MCF7 cells under multiple stress conditions\",\n      \"pmids\": [\"12203114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector mechanism unknown at this stage\", \"No interacting partners identified\", \"p53-independent induction pathway not molecularly defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Sesn2 knockout mice in two sepsis models, co-immunoprecipitation, macrophage inflammasome assays\",\n      \"pmids\": [\"27337507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SESN2–ULK1 binding interface not mapped\", \"Relative contribution of SQSTM1 aggregation versus ULK1 stabilization not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP and luciferase reporter assays in bladder cancer cells with JNK1 inhibitors and siRNA knockdown\",\n      \"pmids\": [\"27171279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AP-1 cooperates with or substitutes for p53 at the SESN2 promoter not determined\", \"Other AP-1 family members not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP for LSD1 at SESN2 promoter, LSD1 inhibitors/shRNA, SESN2 knockdown rescue in neuroblastoma cells\",\n      \"pmids\": [\"28783174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, SESN2 siRNA, ULK1 interaction assays, PINK1 epistasis in multiple cell types\",\n      \"pmids\": [\"29330382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SESN2 directly bridges ULK1 and Beclin1 or acts allosterically not resolved\", \"Structural basis of SESN2–ULK1 interaction unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, K48-linkage-specific ubiquitination assay, RBX1 siRNA stabilization of SESN2\",\n      \"pmids\": [\"29294217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific lysine residues on SESN2 targeted by RBX1 not identified\", \"CRL complex composition (Cullin partner, substrate adaptor) not defined\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"ATF4 knockdown blocking BDNF-induced SESN2 in neuronal cultures, TrkB inhibitors, transcriptomics\",\n      \"pmids\": [\"29599707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATF4 binds directly to the SESN2 promoter in this context not shown by ChIP\", \"Functional neuroprotective readout downstream of SESN2 not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"sgRNA SESN2 knockout, co-immunoprecipitation with Parkin and p62, mitophagy assays, echocardiography in doxorubicin cardiotoxicity model\",\n      \"pmids\": [\"31199952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SESN2 forms a ternary complex with Parkin and p62 simultaneously versus sequential interactions not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mitochondrial fractionation, subcellular localization assays, live-cell imaging\",\n      \"pmids\": [\"32287270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mitochondrial targeting (signal sequence or protein interaction) not identified\", \"Whether localization is constitutive or stress-dependent not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP for H3K27me3 and H3K9me3 at SESN2 promoter, JMJD3/SETDB1 knockdown/overexpression rescue, in vivo cardiac and renal models\",\n      \"pmids\": [\"33117796\", \"39443993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"SESN2−/− mice, immunoprecipitation of AMPK–LKB1 complex, overexpression/inhibition in C2C12 myotubes\",\n      \"pmids\": [\"36994173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SESN2 acts as a direct scaffold bridging LKB1 and AMPK or alters their conformations not determined\", \"Single-lab finding awaits independent replication\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain deletion mutagenesis, co-IP, Sesn2−/− mice in intervertebral disc degeneration model, PINK1 epistasis\",\n      \"pmids\": [\"36632468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural resolution of SESN2 domains binding Parkin and p62 lacking\", \"Whether these domains function independently or cooperatively not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation of SESN2–SCAP, AAV-mediated overexpression in DMM mouse model\",\n      \"pmids\": [\"40822351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SESN2–SCAP interaction is direct or mediated by a complex not established\", \"Binding domain on SESN2 for SCAP not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"SESN1/2 double KO in A549 cells, STAT3 phosphorylation and PTPRD expression analysis\",\n      \"pmids\": [\"39985075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SESN2 maintains PTPRD expression not defined\", \"Whether SESN2 directly regulates PTPRD transcription or protein stability unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"MeRIP-seq identifying m6A at exon 9, IGF2BP1 RIP, mRNA stability assays upon FTO knockdown in NSCLC cells\",\n      \"pmids\": [\"38495179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation of vCyclin–SESN2–OTUB1, site-directed mutagenesis (vCyclin K74), ubiquitination assay in PEL cells\",\n      \"pmids\": [\"41196342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OTUB1 regulates endogenous SESN2 turnover in the absence of vCyclin not tested\", \"Relationship between OTUB1 and RBX1-mediated degradation not examined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation of SESN2–KEAP1, SESN2 siRNA abolishing galangin-induced NRF2 activation, in vivo mouse model\",\n      \"pmids\": [\"41605867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SESN2 competes with NRF2 for the same KEAP1 binding site not structurally resolved\", \"Stoichiometry of SESN2–KEAP1 interaction not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 16, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 19, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 3, 4, 6, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 16, 19]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 10, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [26, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PRKN\",\n      \"SQSTM1\",\n      \"ULK1\",\n      \"KEAP1\",\n      \"SCAP\",\n      \"RBX1\",\n      \"LKB1\",\n      \"OTUB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}