{"gene":"SIRT1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2009,"finding":"AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in SIRT1-mediated deacetylation of PGC-1α, FOXO1, and FOXO3a, thereby coordinating energy metabolism gene expression in skeletal muscle.","method":"Biochemical NAD+ measurement, in vivo mouse studies, deacetylation assays of downstream targets","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (NAD+ measurement, in vivo mouse model, deacetylation assays of multiple substrates), widely replicated across the field","pmids":["19262508"],"is_preprint":false},{"year":2007,"finding":"SIRT1 directly interacts with and deacetylates LXR nuclear receptors at a conserved lysine (K432 in LXRα, K433 in LXRβ), promoting subsequent LXR ubiquitination and activating LXR target genes including the cholesterol transporter ABCA1; mutation of K432 abolishes LXRα activation by SIRT1.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis, LXR target gene expression analysis in SIRT1-deficient cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deacetylation assay with mutagenesis, reciprocal Co-IP, and loss-of-function in vivo, single lab but multiple orthogonal methods","pmids":["17936707"],"is_preprint":false},{"year":2007,"finding":"SIRT1 physically complexes with DNA repair protein Ku70 and deacetylates it; catalytically inactive dominant-negative SIRT1 fails to deacetylate Ku70 or enhance DNA repair capacity after radiation, establishing SIRT1's enzymatic activity as required for Ku70 deacetylation-dependent DNA repair.","method":"Co-immunoprecipitation, dominant-negative SIRT1 mutant, siRNA knockdown, DNA strand break repair assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, dominant-negative mutagenesis, and functional DNA repair assay in single lab","pmids":["17334224"],"is_preprint":false},{"year":2008,"finding":"SIRT1 is phosphorylated at 13 residues in vivo; dephosphorylation by phosphatases reduces NAD+-dependent deacetylase activity; cyclin B/CDK1 forms a complex with SIRT1 and phosphorylates it, with mutation of T530 and S540 (CDK1 sites) disturbing cell cycle progression and failing to rescue proliferation defects in SIRT1-deficient cells.","method":"Mass spectrometry identification of phosphorylation sites, in vitro phosphatase treatment with deacetylase activity assay, co-immunoprecipitation of cyclin B/CDK1 with SIRT1, site-directed mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme activity assay, mass spectrometry, Co-IP of kinase complex, mutagenesis with functional cell cycle readout, multiple orthogonal methods in one study","pmids":["19107194"],"is_preprint":false},{"year":2010,"finding":"Laminar shear stress increases SIRT1 association with eNOS and promotes SIRT1-mediated deacetylation of eNOS; AMPK phosphorylation of eNOS at Ser-633/Ser-1177 is required to prime SIRT1-induced eNOS deacetylation and enhance NO production; AMPKα2-/- mice show elevated eNOS acetylation.","method":"Co-immunoprecipitation, eNOS phosphorylation-site mutants, AMPK inhibitor, in vivo AMPKα2 knockout mouse acetylation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phospho-site mutagenesis, pharmacological inhibition, and in vivo genetic mouse model, multiple orthogonal methods validated in vivo","pmids":["20479254"],"is_preprint":false},{"year":2015,"finding":"SIRT1 deacetylates RORγt, the signature transcription factor of Th17 cells, increasing RORγt transcriptional activity and enhancing Th17 cell generation and function; T cell-specific Sirt1 deletion and pharmacological SIRT1 inhibition suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis.","method":"SIRT1-RORγt co-immunoprecipitation, deacetylation assay, T cell-specific Sirt1 knockout mice, mixed hematopoietic chimeras, EAE mouse model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, deacetylation assay, conditional knockout mouse model, in vivo disease model, and chimera experiments across multiple orthogonal methods","pmids":["25918343"],"is_preprint":false},{"year":2019,"finding":"SIRT1 interacts with CHK2 and deacetylates it at K520, suppressing CHK2 phosphorylation, dimerization, and activation; SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest; genetic deletion of Chk2 rescues the neonatal lethality of Sirt1-/- mice, placing SIRT1 upstream of CHK2 in cell cycle control.","method":"Co-immunoprecipitation, deacetylation assay, CHK2 phosphorylation/dimerization analysis, siRNA/genetic KO, epistasis via Chk2/Sirt1 double-knockout mice","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deacetylation, Co-IP, site-specific mutation, and genetic epistasis rescue in vivo","pmids":["31209362"],"is_preprint":false},{"year":2019,"finding":"SIRT1 binds and deacetylates XRCC1 at K260, K298, and K431, preventing β-TrCP-dependent ubiquitination and proteasomal degradation of XRCC1; mutations at these lysines abrogate β-TrCP interaction and prolong XRCC1 half-life; SIRT1 knockdown reverses chemoresistance by enhancing XRCC1 degradation.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis, ubiquitination assay, siRNA knockdown, chemoresistance functional assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deacetylation, mutagenesis mapping three lysine sites, ubiquitination rescue, and functional chemoresistance assay in single lab with multiple orthogonal methods","pmids":["31043584"],"is_preprint":false},{"year":2020,"finding":"During cellular senescence, nuclear SIRT1 is recognized as an autophagy substrate via a direct SIRT1-LC3 interaction, shuttled from nucleus to cytoplasm, and degraded through the autophagosome-lysosome pathway; this mechanism also operates in vivo during aging of hematopoietic and immune organs in mice and in aged human CD8+CD28- T cells.","method":"Nuclear autophagy substrate identification, SIRT1-LC3 co-immunoprecipitation, live-cell imaging of nucleus-to-cytoplasm shuttling, lysosomal inhibitor experiments, in vivo mouse aging tissues and human aged T cell analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, live imaging, pharmacological inhibition, in vivo mouse and human validation, multiple orthogonal methods replicated in vivo","pmids":["32989246"],"is_preprint":false},{"year":2021,"finding":"SIRT1 directly interacts with and deacetylates HIF-2α; conditional knockout of Sirt1 in renal interstitial cells increases HIF-2α expression and exacerbates renal fibrosis in UUO mice; pharmacological SIRT1 activation decreases HIF-2α and fibrotic gene expression in cultured renal cells.","method":"Co-immunoprecipitation, deacetylation assay, conditional Sirt1 knockout mice, Hif2a knockout epistasis, in vitro SIRT1 activator/inhibitor treatment","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct interaction, deacetylation assay, conditional KO in vivo, and genetic epistasis with Hif2a KO","pmids":["33758176"],"is_preprint":false},{"year":2021,"finding":"SIRT1 deacetylates p62 at K295, preventing Keap1-mediated poly-ubiquitination and proteasomal degradation of p62; acetylated p62 increases its interaction with E3 ligase Keap1; hepatocyte-specific Sirt1 knockout mice develop fewer liver tumors after DEN treatment, reversed by exogenous p62 re-introduction.","method":"Co-immunoprecipitation, deacetylation assay at K295, ubiquitination assay, hepatocyte-specific Sirt1 conditional KO mice, DEN carcinogenesis model, p62 rescue experiment","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — deacetylation site mapping, ubiquitination rescue, conditional KO in vivo, and epistasis rescue via p62 re-expression","pmids":["33854041"],"is_preprint":false},{"year":2023,"finding":"SIRT1 associates with and deacetylates WEE1 kinase, maintaining it in an inactive state; SIRT1 deficiency induces WEE1 hyperacetylation at K177 and activation, rendering cancer cells resistant to WEE1 inhibition; CHK1-dependent phosphorylation of WEE1 at S642 primes GCN5-mediated acetylation at K177 which activates WEE1, counteracted by SIRT1.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis at K177, kinase activity assay, SIRT1 knockdown, genetic loss-of-function with WEE1 inhibitor sensitivity","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic deacetylation, mutagenesis, Co-IP, kinase activity assay, multiple orthogonal methods in single rigorous study","pmids":["36635566"],"is_preprint":false},{"year":2019,"finding":"SIRT1 loss in skeletal muscle activates NF-κB signaling, which enhances FOXO transcription factor expression and NADPH oxidase 4 (NOX4) expression, driving reactive oxygen species production and cancer cachexia; rescuing SIRT1 expression or knocking out Nox4 abrogates tumor-induced muscle wasting in mice.","method":"RNA-seq, exogenous SIRT1 expression rescue, pharmacological SIRT1 activator, Nox4 muscle-specific knockout mice, in vitro myotube wasting assay, tumor-bearing mouse model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-seq pathway identification, genetic KO epistasis, pharmacological and genetic rescue, in vivo mouse model, multiple orthogonal methods","pmids":["32441762"],"is_preprint":false},{"year":2019,"finding":"SIRT1 deletion in CML mice reduces mitochondrial oxidative phosphorylation in leukemia stem cells (LSCs); the SIRT1 substrate PGC-1α contributes to increased oxidative phosphorylation and TKI resistance in CML LSCs; mitochondrial alterations are BCR-ABL kinase-independent.","method":"Conditional Sirt1 deletion in transgenic CML mice, mitochondrial respiration measurement, PGC-1α substrate analysis, TKI treatment of SIRT1-deleted mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic conditional KO in vivo, substrate (PGC-1α) functional analysis, mitochondrial respiration assay, and TKI epistasis experiment","pmids":["31180336"],"is_preprint":false},{"year":2011,"finding":"SIRT1 inhibition blocks FoxO1-dependent DNA repair (GADD45α expression) in β-cells exposed to nitric oxide, and shifts FoxO1 toward a proapoptotic program including PUMA mRNA accumulation and caspase-3 cleavage; FoxO1 nuclear translocation and transcriptional activation in response to nitric oxide is regulated by SIRT1.","method":"SIRT1 pharmacological inhibitors, FoxO1 subcellular localization tracking, GADD45α and PUMA mRNA measurement, caspase-3 cleavage assay, DNA repair assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition, subcellular localization, and multiple functional readouts, single lab","pmids":["21196578"],"is_preprint":false},{"year":2017,"finding":"SIRT1 binds in the β-globin gene cluster locus control region (LCR) and HBG promoters, promotes LCR looping to the HBG promoter, and increases RNA polymerase II and H4K16Ac binding at HBG promoter; SIRT1 suppresses expression of HBG suppressors BCL11A, KLF1, HDAC1, and HDAC2 to activate fetal hemoglobin (γ-globin) gene expression.","method":"ChIP for SIRT1 at LCR and HBG promoters, chromosome conformation/looping assay, SIRT1 knockdown/ectopic expression, small molecule SIRT1 activators, RNA polymerase II ChIP","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, chromatin looping assay, gain/loss of function, pharmacological activation, multiple orthogonal methods in single lab","pmids":["28776729"],"is_preprint":false},{"year":2017,"finding":"SIRT1 positively affects macrophage self-renewal by regulating G1/S cell cycle transition; SIRT1 inhibition activates FOXO1 and suppresses E2F1 and Myc (known SIRT1 targets mediating cell cycle progression), restricting macrophage proliferation both in vitro and in vivo.","method":"SIRT1 overexpression/shRNA knockdown/CRISPR-Cas9 deletion, pharmacological inhibition, in vivo alveolar and peritoneal macrophage proliferation assay, cell cycle analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss of function (shRNA, CRISPR, OE), pharmacological inhibition, in vivo validation, single lab with multiple orthogonal approaches","pmids":["28701484"],"is_preprint":false},{"year":2019,"finding":"SIRT1 deacetylates STAT3, leading to STAT3 destabilization and degradation, thereby reducing FGB expression and inhibiting renal cell carcinoma (RCC) proliferation; co-immunoprecipitation confirmed SIRT1-STAT3 physical interaction.","method":"Co-immunoprecipitation, Western blot for STAT3 protein stability, SIRT1 overexpression, luciferase reporter for FGB as STAT3 target, in vitro and in vivo proliferation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, protein stability assay, SIRT1 overexpression with functional tumor readout, single lab","pmids":["31201813"],"is_preprint":false},{"year":2019,"finding":"SIRT1 deacetylates p21, promoting p21 ubiquitination and degradation, thereby inducing cardiomyocyte proliferation; overexpression of SIRT1 increases EdU-, pH3-, and Aurora B-positive cardiomyocytes in neonatal and adult mice; depletion of SIRT1 reduces cardiomyocyte proliferation in vitro and in vivo.","method":"Deacetylation assay, ubiquitination assay, SIRT1 overexpression/knockdown, EdU/pH3/Aurora B proliferation markers in vitro and in vivo in mouse hearts","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deacetylation and ubiquitination assays, gain/loss of function, in vivo mouse model, single lab","pmids":["31881009"],"is_preprint":false},{"year":2010,"finding":"C/EBPα directly binds to the SIRT1 promoter at a consensus C/EBPα binding site and upregulates SIRT1 mRNA and protein expression during adipogenesis; knockdown of C/EBPα decreases SIRT1 protein levels in preadipocytes.","method":"Promoter deletion analysis, gel shift assay (EMSA), chromatin immunoprecipitation (ChIP), C/EBPα ectopic expression and siRNA knockdown, luciferase reporter assay","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, promoter deletion, and gain/loss of function, single lab with multiple orthogonal methods","pmids":["20157332"],"is_preprint":false},{"year":2016,"finding":"SIRT1 promotes ABCG2 expression in the ileum via deacetylation of PGC-1α, which then activates PPARγ effectors; siRNA blockade of PGC-1α or PPARγ significantly inhibits SIRT1-induced ABCG2 upregulation, demonstrating the PGC-1α/PPARγ-ABCG2 pathway downstream of SIRT1 in uric acid regulation.","method":"siRNA knockdown of PGC-1α and PPARγ, PGC-1α deacetylation assay, in vivo hyperuricemia mouse model with resveratrol treatment, ABCG2 expression analysis","journal":"Endocrine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — deacetylation assay, genetic epistasis via siRNA, in vivo mouse model, single lab","pmids":["27022940"],"is_preprint":false},{"year":2021,"finding":"SIRT1 interacts with ADNP at two sites: one at the microtubule end-binding protein (EB1/EB3)/Tau level and one on chromatin, where ADNP, YY1, and HDAC2 share a DNA-binding motif that regulates SIRT1, ADNP, and EB1 expression; this ADNP-SIRT1 complex is linked to sex- and age-dependent histone modification via WDR5.","method":"Co-immunoprecipitation of ADNP-SIRT1 complex, single-cell RNA and protein expression analysis, gene expression correlation in mouse/human brain, chromatin binding motif analysis","journal":"Molecular psychiatry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and expression correlation, mechanistic detail limited in abstract, single lab","pmids":["33967268"],"is_preprint":false}],"current_model":"SIRT1 is an NAD+-dependent protein deacetylase that acts as a central metabolic and stress sensor, directly deacetylating a broad range of histone and non-histone substrates—including PGC-1α, FOXO transcription factors, LXR, eNOS, RORγt, CHK2, WEE1, Ku70, XRCC1, HIF-2α, STAT3, p21, p62, and others—to regulate energy metabolism, cell cycle progression, DNA repair, inflammation, and cell survival; its activity is modulated upstream by cellular NAD+ levels (raised by AMPK), by CDK1-mediated phosphorylation, and by autophagic degradation via a direct SIRT1-LC3 interaction during senescence and aging."},"narrative":{"mechanistic_narrative":"SIRT1 is an NAD+-dependent protein deacetylase that functions as a central metabolic and stress sensor, coupling cellular energy status to the post-translational control of a broad set of histone and non-histone substrates [PMID:19262508]. Its activity is set upstream by NAD+ availability—raised by AMPK to drive deacetylation of the metabolic regulators PGC-1α, FOXO1, and FOXO3a [PMID:19262508]—and by cyclin B/CDK1-mediated phosphorylation at T530/S540, which is required for normal cell cycle progression [PMID:19107194]. Through substrate deacetylation, SIRT1 tunes energy metabolism and mitochondrial oxidative phosphorylation via PGC-1α [PMID:19262508, PMID:31180336], regulates nuclear receptor and vascular signaling by deacetylating LXR to activate ABCA1-dependent cholesterol transport [PMID:17936707] and eNOS to enhance NO production downstream of shear-stress/AMPK priming [PMID:20479254], and shapes immune and inflammatory programs by deacetylating RORγt to promote Th17 differentiation [PMID:25918343] and by restraining NF-κB/FOXO/NOX4-driven muscle wasting [PMID:32441762]. A recurring mechanistic theme is SIRT1 control of protein stability: deacetylation blocks degradation of XRCC1 and p62 by preventing β-TrCP- and Keap1-mediated ubiquitination [PMID:31043584, PMID:33854041], while promoting degradation of p21 and STAT3 to drive proliferation [PMID:31201813, PMID:31881009]. In cell cycle and DNA-damage control SIRT1 acts upstream of the checkpoint machinery, deacetylating and suppressing CHK2 and WEE1—epistasis with Chk2 rescues Sirt1-null neonatal lethality—and deacetylating Ku70 to support DNA double-strand break repair [PMID:17334224, PMID:31209362, PMID:36635566]. SIRT1 itself is removed during senescence and aging through a direct SIRT1–LC3 interaction that targets nuclear SIRT1 for autophagosomal–lysosomal degradation [PMID:32989246].","teleology":[{"year":2007,"claim":"Established SIRT1 as a deacetylase of non-histone signaling substrates by showing it directly deacetylates LXR nuclear receptors and the DNA-repair factor Ku70, extending its role beyond chromatin.","evidence":"Co-IP, in vitro deacetylation assays, site-directed mutagenesis (LXRα K432), dominant-negative SIRT1, and DNA strand-break repair assays","pmids":["17936707","17334224"],"confidence":"High","gaps":["Direct enzymatic requirement for Ku70 deacetylation shown only with dominant-negative SIRT1, not site-mapped acetyl-lysine","Physiological NAD+ dependence of LXR/Ku70 deacetylation not addressed in these studies"]},{"year":2008,"claim":"Resolved how SIRT1 catalytic activity is regulated post-translationally, identifying multisite phosphorylation and CDK1 as a direct kinase controlling its deacetylase activity and cell-cycle function.","evidence":"Mass spectrometry of 13 phosphosites, phosphatase treatment with deacetylase activity assay, cyclin B/CDK1 Co-IP, and T530/S540 mutagenesis with cell-cycle readout","pmids":["19107194"],"confidence":"High","gaps":["Structural basis for how phosphorylation modulates catalysis not defined","Functions of the remaining phosphosites beyond T530/S540 unresolved"]},{"year":2009,"claim":"Placed SIRT1 within an upstream metabolic-sensing circuit by showing AMPK raises NAD+ to activate SIRT1-dependent deacetylation of PGC-1α and FOXOs, coordinating energy-metabolism gene expression.","evidence":"Biochemical NAD+ measurement, in vivo mouse skeletal muscle studies, and deacetylation assays of multiple substrates","pmids":["19262508"],"confidence":"High","gaps":["Quantitative contribution of NAD+ flux versus other inputs to SIRT1 activation not partitioned","Tissue-specific differences in the AMPK–NAD+–SIRT1 axis not mapped"]},{"year":2010,"claim":"Extended SIRT1 into vascular and adipogenic contexts, showing AMPK-primed phosphorylation of eNOS enables SIRT1 deacetylation and NO production, and that C/EBPα transcriptionally induces SIRT1 during adipogenesis.","evidence":"Co-IP, eNOS phospho-site mutants, AMPKα2-/- mice (eNOS); promoter deletion, EMSA, ChIP, and C/EBPα gain/loss of function (SIRT1 expression)","pmids":["20479254","20157332"],"confidence":"High","gaps":["C/EBPα–SIRT1 regulation is Medium-confidence and from a single lab","Crosstalk between transcriptional SIRT1 induction and post-translational activation not integrated"]},{"year":2015,"claim":"Defined a substrate-level mechanism linking SIRT1 to adaptive immunity by showing deacetylation of RORγt enhances Th17 differentiation and autoimmune disease in vivo.","evidence":"Co-IP, deacetylation assay, T-cell-specific Sirt1 knockout mice, hematopoietic chimeras, and EAE model","pmids":["25918343"],"confidence":"High","gaps":["RORγt acetyl-lysine site not specified","Relationship to other SIRT1 immune substrates (e.g. NF-κB) not reconciled"]},{"year":2019,"claim":"Positioned SIRT1 upstream of the DNA-damage checkpoint and protein-stability control, showing it deacetylates CHK2 (K520) to restrain its activation, deacetylates XRCC1 to block β-TrCP-dependent degradation, and destabilizes STAT3 and p21 to drive proliferation.","evidence":"Co-IP, in vitro deacetylation and ubiquitination assays, site mapping, Chk2/Sirt1 double-knockout epistasis, chemoresistance and proliferation assays in vitro and in vivo","pmids":["31209362","31043584","31201813","31881009"],"confidence":"High","gaps":["Opposing effects of SIRT1 on substrate stability (stabilizing XRCC1/p62 vs destabilizing p21/STAT3) lack a unifying determinant","STAT3 and p21 findings are Medium-confidence single-lab studies"]},{"year":2019,"claim":"Connected SIRT1 substrate deacetylation to disease metabolism, showing PGC-1α-dependent oxidative phosphorylation in CML leukemia stem cells and NF-κB/FOXO/NOX4-driven oxidative muscle wasting upon SIRT1 loss.","evidence":"Conditional Sirt1 deletion in CML and tumor-bearing mice, mitochondrial respiration assays, RNA-seq, Nox4 muscle-specific knockout, and genetic/pharmacological rescue","pmids":["31180336","32441762"],"confidence":"High","gaps":["Direct acetylation targets within the NF-κB/FOXO/NOX4 axis not fully resolved","Whether mitochondrial and inflammatory phenotypes share common SIRT1 substrates unaddressed"]},{"year":2020,"claim":"Revealed how SIRT1 protein levels decline with age, identifying nuclear SIRT1 as a direct LC3-bound autophagy substrate that is shuttled to the cytoplasm and degraded during senescence.","evidence":"SIRT1-LC3 Co-IP, live-cell imaging of nucleo-cytoplasmic shuttling, lysosomal inhibitors, and validation in aged mouse tissues and human CD8+CD28- T cells","pmids":["32989246"],"confidence":"High","gaps":["Signal that designates nuclear SIRT1 for LC3 recognition not defined","Whether catalytic activity or modification state gates autophagic targeting unknown"]},{"year":2021,"claim":"Broadened SIRT1's substrate range to hypoxia and selective autophagy, showing deacetylation of HIF-2α limits renal fibrosis and deacetylation of p62 (K295) blocks Keap1-mediated degradation to influence liver tumorigenesis.","evidence":"Co-IP, deacetylation and ubiquitination assays, conditional Sirt1 knockout mice, Hif2a epistasis, and DEN carcinogenesis with p62 rescue","pmids":["33758176","33854041"],"confidence":"High","gaps":["HIF-2α acetyl-lysine site not mapped","Context determining whether SIRT1 acts as tumor suppressor or promoter not resolved"]},{"year":2023,"claim":"Defined a phospho-acetyl switch on WEE1 controlled by SIRT1, showing CHK1-primed, GCN5-mediated K177 acetylation activates WEE1 while SIRT1 deacetylation maintains it inactive, with implications for WEE1-inhibitor resistance.","evidence":"Co-IP, in vitro deacetylation, K177 mutagenesis, kinase activity assays, and SIRT1 knockdown with WEE1-inhibitor sensitivity","pmids":["36635566"],"confidence":"High","gaps":["In vivo relevance to tumor responses to WEE1 inhibition not established here","Interplay between SIRT1 control of CHK2 and WEE1 in the same checkpoint not integrated"]},{"year":null,"claim":"How a single deacetylase selects among its many competing substrates in a given cell state, and what determines whether deacetylation stabilizes or destabilizes a target, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selection across metabolic, checkpoint, and immune contexts","Determinants of opposing stability outcomes (XRCC1/p62 stabilized vs p21/STAT3 destabilized) not defined","Quantitative coupling between NAD+/phosphorylation inputs and substrate-specific output not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,6,7,9,10,11,17,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,6,7,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,13,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6,11,16,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,7,14]},{"term_id":"R-HSA-168256","term_label":"Immune 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medicine.","date":"2010","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21497775","citation_count":37,"is_preprint":false},{"pmid":"28781601","id":"PMC_28781601","title":"Resveratrol Attenuates Microglial Activation via SIRT1-SOCS1 Pathway.","date":"2017","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/28781601","citation_count":37,"is_preprint":false},{"pmid":"28197553","id":"PMC_28197553","title":"The Role of Sirt1 in Epileptogenesis.","date":"2017","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/28197553","citation_count":36,"is_preprint":false},{"pmid":"23519155","id":"PMC_23519155","title":"Roles of SIRT1 in leukemogenesis.","date":"2013","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/23519155","citation_count":35,"is_preprint":false},{"pmid":"31881009","id":"PMC_31881009","title":"Sirt1-inducible deacetylation of p21 promotes cardiomyocyte proliferation.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31881009","citation_count":35,"is_preprint":false},{"pmid":"36503597","id":"PMC_36503597","title":"Irisin enhances longevity by boosting SIRT1, AMPK, autophagy and telomerase.","date":"2022","source":"Expert reviews in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36503597","citation_count":35,"is_preprint":false},{"pmid":"25806122","id":"PMC_25806122","title":"Expression of SIRT1 and SIRT3 varies according to age in mice.","date":"2015","source":"Anatomy & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25806122","citation_count":35,"is_preprint":false},{"pmid":"31201813","id":"PMC_31201813","title":"SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31201813","citation_count":35,"is_preprint":false},{"pmid":"19275731","id":"PMC_19275731","title":"Physiological and pathophysiological functions of SIRT1.","date":"2009","source":"Mini reviews in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19275731","citation_count":34,"is_preprint":false},{"pmid":"25440052","id":"PMC_25440052","title":"Linking DNA damage, NAD(+)/SIRT1, and aging.","date":"2014","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25440052","citation_count":33,"is_preprint":false},{"pmid":"33649834","id":"PMC_33649834","title":"SIRT1 and gynecological malignancies (Review).","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33649834","citation_count":32,"is_preprint":false},{"pmid":"37343148","id":"PMC_37343148","title":"Naringenin ameliorates vascular senescence and atherosclerosis involving SIRT1 activation.","date":"2023","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37343148","citation_count":32,"is_preprint":false},{"pmid":"30393078","id":"PMC_30393078","title":"AHR Regulates Metabolic Reprogramming to Promote SIRT1-Dependent Keratinocyte Differentiation.","date":"2018","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30393078","citation_count":31,"is_preprint":false},{"pmid":"36635566","id":"PMC_36635566","title":"SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.","date":"2023","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36635566","citation_count":30,"is_preprint":false},{"pmid":"26931472","id":"PMC_26931472","title":"Epigenetic Regulation Through SIRT1 in Podocytes.","date":"2016","source":"Current hypertension reviews","url":"https://pubmed.ncbi.nlm.nih.gov/26931472","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41389,"output_tokens":5942,"usd":0.106648,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14661,"output_tokens":4875,"usd":0.09759,"stage2_stop_reason":"end_turn"},"total_usd":0.204238,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in SIRT1-mediated deacetylation of PGC-1α, FOXO1, and FOXO3a, thereby coordinating energy metabolism gene expression in skeletal muscle.\",\n      \"method\": \"Biochemical NAD+ measurement, in vivo mouse studies, deacetylation assays of downstream targets\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (NAD+ measurement, in vivo mouse model, deacetylation assays of multiple substrates), widely replicated across the field\",\n      \"pmids\": [\"19262508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SIRT1 directly interacts with and deacetylates LXR nuclear receptors at a conserved lysine (K432 in LXRα, K433 in LXRβ), promoting subsequent LXR ubiquitination and activating LXR target genes including the cholesterol transporter ABCA1; mutation of K432 abolishes LXRα activation by SIRT1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis, LXR target gene expression analysis in SIRT1-deficient cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deacetylation assay with mutagenesis, reciprocal Co-IP, and loss-of-function in vivo, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17936707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SIRT1 physically complexes with DNA repair protein Ku70 and deacetylates it; catalytically inactive dominant-negative SIRT1 fails to deacetylate Ku70 or enhance DNA repair capacity after radiation, establishing SIRT1's enzymatic activity as required for Ku70 deacetylation-dependent DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative SIRT1 mutant, siRNA knockdown, DNA strand break repair assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, dominant-negative mutagenesis, and functional DNA repair assay in single lab\",\n      \"pmids\": [\"17334224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIRT1 is phosphorylated at 13 residues in vivo; dephosphorylation by phosphatases reduces NAD+-dependent deacetylase activity; cyclin B/CDK1 forms a complex with SIRT1 and phosphorylates it, with mutation of T530 and S540 (CDK1 sites) disturbing cell cycle progression and failing to rescue proliferation defects in SIRT1-deficient cells.\",\n      \"method\": \"Mass spectrometry identification of phosphorylation sites, in vitro phosphatase treatment with deacetylase activity assay, co-immunoprecipitation of cyclin B/CDK1 with SIRT1, site-directed mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme activity assay, mass spectrometry, Co-IP of kinase complex, mutagenesis with functional cell cycle readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19107194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Laminar shear stress increases SIRT1 association with eNOS and promotes SIRT1-mediated deacetylation of eNOS; AMPK phosphorylation of eNOS at Ser-633/Ser-1177 is required to prime SIRT1-induced eNOS deacetylation and enhance NO production; AMPKα2-/- mice show elevated eNOS acetylation.\",\n      \"method\": \"Co-immunoprecipitation, eNOS phosphorylation-site mutants, AMPK inhibitor, in vivo AMPKα2 knockout mouse acetylation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phospho-site mutagenesis, pharmacological inhibition, and in vivo genetic mouse model, multiple orthogonal methods validated in vivo\",\n      \"pmids\": [\"20479254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIRT1 deacetylates RORγt, the signature transcription factor of Th17 cells, increasing RORγt transcriptional activity and enhancing Th17 cell generation and function; T cell-specific Sirt1 deletion and pharmacological SIRT1 inhibition suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis.\",\n      \"method\": \"SIRT1-RORγt co-immunoprecipitation, deacetylation assay, T cell-specific Sirt1 knockout mice, mixed hematopoietic chimeras, EAE mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, deacetylation assay, conditional knockout mouse model, in vivo disease model, and chimera experiments across multiple orthogonal methods\",\n      \"pmids\": [\"25918343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 interacts with CHK2 and deacetylates it at K520, suppressing CHK2 phosphorylation, dimerization, and activation; SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest; genetic deletion of Chk2 rescues the neonatal lethality of Sirt1-/- mice, placing SIRT1 upstream of CHK2 in cell cycle control.\",\n      \"method\": \"Co-immunoprecipitation, deacetylation assay, CHK2 phosphorylation/dimerization analysis, siRNA/genetic KO, epistasis via Chk2/Sirt1 double-knockout mice\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deacetylation, Co-IP, site-specific mutation, and genetic epistasis rescue in vivo\",\n      \"pmids\": [\"31209362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 binds and deacetylates XRCC1 at K260, K298, and K431, preventing β-TrCP-dependent ubiquitination and proteasomal degradation of XRCC1; mutations at these lysines abrogate β-TrCP interaction and prolong XRCC1 half-life; SIRT1 knockdown reverses chemoresistance by enhancing XRCC1 degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis, ubiquitination assay, siRNA knockdown, chemoresistance functional assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deacetylation, mutagenesis mapping three lysine sites, ubiquitination rescue, and functional chemoresistance assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31043584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"During cellular senescence, nuclear SIRT1 is recognized as an autophagy substrate via a direct SIRT1-LC3 interaction, shuttled from nucleus to cytoplasm, and degraded through the autophagosome-lysosome pathway; this mechanism also operates in vivo during aging of hematopoietic and immune organs in mice and in aged human CD8+CD28- T cells.\",\n      \"method\": \"Nuclear autophagy substrate identification, SIRT1-LC3 co-immunoprecipitation, live-cell imaging of nucleus-to-cytoplasm shuttling, lysosomal inhibitor experiments, in vivo mouse aging tissues and human aged T cell analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, live imaging, pharmacological inhibition, in vivo mouse and human validation, multiple orthogonal methods replicated in vivo\",\n      \"pmids\": [\"32989246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT1 directly interacts with and deacetylates HIF-2α; conditional knockout of Sirt1 in renal interstitial cells increases HIF-2α expression and exacerbates renal fibrosis in UUO mice; pharmacological SIRT1 activation decreases HIF-2α and fibrotic gene expression in cultured renal cells.\",\n      \"method\": \"Co-immunoprecipitation, deacetylation assay, conditional Sirt1 knockout mice, Hif2a knockout epistasis, in vitro SIRT1 activator/inhibitor treatment\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct interaction, deacetylation assay, conditional KO in vivo, and genetic epistasis with Hif2a KO\",\n      \"pmids\": [\"33758176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT1 deacetylates p62 at K295, preventing Keap1-mediated poly-ubiquitination and proteasomal degradation of p62; acetylated p62 increases its interaction with E3 ligase Keap1; hepatocyte-specific Sirt1 knockout mice develop fewer liver tumors after DEN treatment, reversed by exogenous p62 re-introduction.\",\n      \"method\": \"Co-immunoprecipitation, deacetylation assay at K295, ubiquitination assay, hepatocyte-specific Sirt1 conditional KO mice, DEN carcinogenesis model, p62 rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — deacetylation site mapping, ubiquitination rescue, conditional KO in vivo, and epistasis rescue via p62 re-expression\",\n      \"pmids\": [\"33854041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT1 associates with and deacetylates WEE1 kinase, maintaining it in an inactive state; SIRT1 deficiency induces WEE1 hyperacetylation at K177 and activation, rendering cancer cells resistant to WEE1 inhibition; CHK1-dependent phosphorylation of WEE1 at S642 primes GCN5-mediated acetylation at K177 which activates WEE1, counteracted by SIRT1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis at K177, kinase activity assay, SIRT1 knockdown, genetic loss-of-function with WEE1 inhibitor sensitivity\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic deacetylation, mutagenesis, Co-IP, kinase activity assay, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36635566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 loss in skeletal muscle activates NF-κB signaling, which enhances FOXO transcription factor expression and NADPH oxidase 4 (NOX4) expression, driving reactive oxygen species production and cancer cachexia; rescuing SIRT1 expression or knocking out Nox4 abrogates tumor-induced muscle wasting in mice.\",\n      \"method\": \"RNA-seq, exogenous SIRT1 expression rescue, pharmacological SIRT1 activator, Nox4 muscle-specific knockout mice, in vitro myotube wasting assay, tumor-bearing mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-seq pathway identification, genetic KO epistasis, pharmacological and genetic rescue, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"32441762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 deletion in CML mice reduces mitochondrial oxidative phosphorylation in leukemia stem cells (LSCs); the SIRT1 substrate PGC-1α contributes to increased oxidative phosphorylation and TKI resistance in CML LSCs; mitochondrial alterations are BCR-ABL kinase-independent.\",\n      \"method\": \"Conditional Sirt1 deletion in transgenic CML mice, mitochondrial respiration measurement, PGC-1α substrate analysis, TKI treatment of SIRT1-deleted mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic conditional KO in vivo, substrate (PGC-1α) functional analysis, mitochondrial respiration assay, and TKI epistasis experiment\",\n      \"pmids\": [\"31180336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIRT1 inhibition blocks FoxO1-dependent DNA repair (GADD45α expression) in β-cells exposed to nitric oxide, and shifts FoxO1 toward a proapoptotic program including PUMA mRNA accumulation and caspase-3 cleavage; FoxO1 nuclear translocation and transcriptional activation in response to nitric oxide is regulated by SIRT1.\",\n      \"method\": \"SIRT1 pharmacological inhibitors, FoxO1 subcellular localization tracking, GADD45α and PUMA mRNA measurement, caspase-3 cleavage assay, DNA repair assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition, subcellular localization, and multiple functional readouts, single lab\",\n      \"pmids\": [\"21196578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT1 binds in the β-globin gene cluster locus control region (LCR) and HBG promoters, promotes LCR looping to the HBG promoter, and increases RNA polymerase II and H4K16Ac binding at HBG promoter; SIRT1 suppresses expression of HBG suppressors BCL11A, KLF1, HDAC1, and HDAC2 to activate fetal hemoglobin (γ-globin) gene expression.\",\n      \"method\": \"ChIP for SIRT1 at LCR and HBG promoters, chromosome conformation/looping assay, SIRT1 knockdown/ectopic expression, small molecule SIRT1 activators, RNA polymerase II ChIP\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, chromatin looping assay, gain/loss of function, pharmacological activation, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"28776729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT1 positively affects macrophage self-renewal by regulating G1/S cell cycle transition; SIRT1 inhibition activates FOXO1 and suppresses E2F1 and Myc (known SIRT1 targets mediating cell cycle progression), restricting macrophage proliferation both in vitro and in vivo.\",\n      \"method\": \"SIRT1 overexpression/shRNA knockdown/CRISPR-Cas9 deletion, pharmacological inhibition, in vivo alveolar and peritoneal macrophage proliferation assay, cell cycle analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss of function (shRNA, CRISPR, OE), pharmacological inhibition, in vivo validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"28701484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 deacetylates STAT3, leading to STAT3 destabilization and degradation, thereby reducing FGB expression and inhibiting renal cell carcinoma (RCC) proliferation; co-immunoprecipitation confirmed SIRT1-STAT3 physical interaction.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for STAT3 protein stability, SIRT1 overexpression, luciferase reporter for FGB as STAT3 target, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, protein stability assay, SIRT1 overexpression with functional tumor readout, single lab\",\n      \"pmids\": [\"31201813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT1 deacetylates p21, promoting p21 ubiquitination and degradation, thereby inducing cardiomyocyte proliferation; overexpression of SIRT1 increases EdU-, pH3-, and Aurora B-positive cardiomyocytes in neonatal and adult mice; depletion of SIRT1 reduces cardiomyocyte proliferation in vitro and in vivo.\",\n      \"method\": \"Deacetylation assay, ubiquitination assay, SIRT1 overexpression/knockdown, EdU/pH3/Aurora B proliferation markers in vitro and in vivo in mouse hearts\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deacetylation and ubiquitination assays, gain/loss of function, in vivo mouse model, single lab\",\n      \"pmids\": [\"31881009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C/EBPα directly binds to the SIRT1 promoter at a consensus C/EBPα binding site and upregulates SIRT1 mRNA and protein expression during adipogenesis; knockdown of C/EBPα decreases SIRT1 protein levels in preadipocytes.\",\n      \"method\": \"Promoter deletion analysis, gel shift assay (EMSA), chromatin immunoprecipitation (ChIP), C/EBPα ectopic expression and siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, promoter deletion, and gain/loss of function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20157332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT1 promotes ABCG2 expression in the ileum via deacetylation of PGC-1α, which then activates PPARγ effectors; siRNA blockade of PGC-1α or PPARγ significantly inhibits SIRT1-induced ABCG2 upregulation, demonstrating the PGC-1α/PPARγ-ABCG2 pathway downstream of SIRT1 in uric acid regulation.\",\n      \"method\": \"siRNA knockdown of PGC-1α and PPARγ, PGC-1α deacetylation assay, in vivo hyperuricemia mouse model with resveratrol treatment, ABCG2 expression analysis\",\n      \"journal\": \"Endocrine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — deacetylation assay, genetic epistasis via siRNA, in vivo mouse model, single lab\",\n      \"pmids\": [\"27022940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT1 interacts with ADNP at two sites: one at the microtubule end-binding protein (EB1/EB3)/Tau level and one on chromatin, where ADNP, YY1, and HDAC2 share a DNA-binding motif that regulates SIRT1, ADNP, and EB1 expression; this ADNP-SIRT1 complex is linked to sex- and age-dependent histone modification via WDR5.\",\n      \"method\": \"Co-immunoprecipitation of ADNP-SIRT1 complex, single-cell RNA and protein expression analysis, gene expression correlation in mouse/human brain, chromatin binding motif analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and expression correlation, mechanistic detail limited in abstract, single lab\",\n      \"pmids\": [\"33967268\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT1 is an NAD+-dependent protein deacetylase that acts as a central metabolic and stress sensor, directly deacetylating a broad range of histone and non-histone substrates—including PGC-1α, FOXO transcription factors, LXR, eNOS, RORγt, CHK2, WEE1, Ku70, XRCC1, HIF-2α, STAT3, p21, p62, and others—to regulate energy metabolism, cell cycle progression, DNA repair, inflammation, and cell survival; its activity is modulated upstream by cellular NAD+ levels (raised by AMPK), by CDK1-mediated phosphorylation, and by autophagic degradation via a direct SIRT1-LC3 interaction during senescence and aging.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRT1 is an NAD+-dependent protein deacetylase that functions as a central metabolic and stress sensor, coupling cellular energy status to the post-translational control of a broad set of histone and non-histone substrates [#0]. Its activity is set upstream by NAD+ availability—raised by AMPK to drive deacetylation of the metabolic regulators PGC-1\\u03b1, FOXO1, and FOXO3a [#0]—and by cyclin B/CDK1-mediated phosphorylation at T530/S540, which is required for normal cell cycle progression [#3]. Through substrate deacetylation, SIRT1 tunes energy metabolism and mitochondrial oxidative phosphorylation via PGC-1\\u03b1 [#0, #13], regulates nuclear receptor and vascular signaling by deacetylating LXR to activate ABCA1-dependent cholesterol transport [#1] and eNOS to enhance NO production downstream of shear-stress/AMPK priming [#4], and shapes immune and inflammatory programs by deacetylating ROR\\u03b3t to promote Th17 differentiation [#5] and by restraining NF-\\u03baB/FOXO/NOX4-driven muscle wasting [#12]. A recurring mechanistic theme is SIRT1 control of protein stability: deacetylation blocks degradation of XRCC1 and p62 by preventing \\u03b2-TrCP- and Keap1-mediated ubiquitination [#7, #10], while promoting degradation of p21 and STAT3 to drive proliferation [#17, #18]. In cell cycle and DNA-damage control SIRT1 acts upstream of the checkpoint machinery, deacetylating and suppressing CHK2 and WEE1—epistasis with Chk2 rescues Sirt1-null neonatal lethality—and deacetylating Ku70 to support DNA double-strand break repair [#2, #6, #11]. SIRT1 itself is removed during senescence and aging through a direct SIRT1\\u2013LC3 interaction that targets nuclear SIRT1 for autophagosomal\\u2013lysosomal degradation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established SIRT1 as a deacetylase of non-histone signaling substrates by showing it directly deacetylates LXR nuclear receptors and the DNA-repair factor Ku70, extending its role beyond chromatin.\",\n      \"evidence\": \"Co-IP, in vitro deacetylation assays, site-directed mutagenesis (LXR\\u03b1 K432), dominant-negative SIRT1, and DNA strand-break repair assays\",\n      \"pmids\": [\n        \"17936707\",\n        \"17334224\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct enzymatic requirement for Ku70 deacetylation shown only with dominant-negative SIRT1, not site-mapped acetyl-lysine\",\n        \"Physiological NAD+ dependence of LXR/Ku70 deacetylation not addressed in these studies\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how SIRT1 catalytic activity is regulated post-translationally, identifying multisite phosphorylation and CDK1 as a direct kinase controlling its deacetylase activity and cell-cycle function.\",\n      \"evidence\": \"Mass spectrometry of 13 phosphosites, phosphatase treatment with deacetylase activity assay, cyclin B/CDK1 Co-IP, and T530/S540 mutagenesis with cell-cycle readout\",\n      \"pmids\": [\n        \"19107194\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how phosphorylation modulates catalysis not defined\",\n        \"Functions of the remaining phosphosites beyond T530/S540 unresolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed SIRT1 within an upstream metabolic-sensing circuit by showing AMPK raises NAD+ to activate SIRT1-dependent deacetylation of PGC-1\\u03b1 and FOXOs, coordinating energy-metabolism gene expression.\",\n      \"evidence\": \"Biochemical NAD+ measurement, in vivo mouse skeletal muscle studies, and deacetylation assays of multiple substrates\",\n      \"pmids\": [\n        \"19262508\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative contribution of NAD+ flux versus other inputs to SIRT1 activation not partitioned\",\n        \"Tissue-specific differences in the AMPK\\u2013NAD+\\u2013SIRT1 axis not mapped\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended SIRT1 into vascular and adipogenic contexts, showing AMPK-primed phosphorylation of eNOS enables SIRT1 deacetylation and NO production, and that C/EBP\\u03b1 transcriptionally induces SIRT1 during adipogenesis.\",\n      \"evidence\": \"Co-IP, eNOS phospho-site mutants, AMPK\\u03b12-/- mice (eNOS); promoter deletion, EMSA, ChIP, and C/EBP\\u03b1 gain/loss of function (SIRT1 expression)\",\n      \"pmids\": [\n        \"20479254\",\n        \"20157332\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"C/EBP\\u03b1\\u2013SIRT1 regulation is Medium-confidence and from a single lab\",\n        \"Crosstalk between transcriptional SIRT1 induction and post-translational activation not integrated\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a substrate-level mechanism linking SIRT1 to adaptive immunity by showing deacetylation of ROR\\u03b3t enhances Th17 differentiation and autoimmune disease in vivo.\",\n      \"evidence\": \"Co-IP, deacetylation assay, T-cell-specific Sirt1 knockout mice, hematopoietic chimeras, and EAE model\",\n      \"pmids\": [\n        \"25918343\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"ROR\\u03b3t acetyl-lysine site not specified\",\n        \"Relationship to other SIRT1 immune substrates (e.g. NF-\\u03baB) not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned SIRT1 upstream of the DNA-damage checkpoint and protein-stability control, showing it deacetylates CHK2 (K520) to restrain its activation, deacetylates XRCC1 to block \\u03b2-TrCP-dependent degradation, and destabilizes STAT3 and p21 to drive proliferation.\",\n      \"evidence\": \"Co-IP, in vitro deacetylation and ubiquitination assays, site mapping, Chk2/Sirt1 double-knockout epistasis, chemoresistance and proliferation assays in vitro and in vivo\",\n      \"pmids\": [\n        \"31209362\",\n        \"31043584\",\n        \"31201813\",\n        \"31881009\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Opposing effects of SIRT1 on substrate stability (stabilizing XRCC1/p62 vs destabilizing p21/STAT3) lack a unifying determinant\",\n        \"STAT3 and p21 findings are Medium-confidence single-lab studies\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SIRT1 substrate deacetylation to disease metabolism, showing PGC-1\\u03b1-dependent oxidative phosphorylation in CML leukemia stem cells and NF-\\u03baB/FOXO/NOX4-driven oxidative muscle wasting upon SIRT1 loss.\",\n      \"evidence\": \"Conditional Sirt1 deletion in CML and tumor-bearing mice, mitochondrial respiration assays, RNA-seq, Nox4 muscle-specific knockout, and genetic/pharmacological rescue\",\n      \"pmids\": [\n        \"31180336\",\n        \"32441762\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct acetylation targets within the NF-\\u03baB/FOXO/NOX4 axis not fully resolved\",\n        \"Whether mitochondrial and inflammatory phenotypes share common SIRT1 substrates unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed how SIRT1 protein levels decline with age, identifying nuclear SIRT1 as a direct LC3-bound autophagy substrate that is shuttled to the cytoplasm and degraded during senescence.\",\n      \"evidence\": \"SIRT1-LC3 Co-IP, live-cell imaging of nucleo-cytoplasmic shuttling, lysosomal inhibitors, and validation in aged mouse tissues and human CD8+CD28- T cells\",\n      \"pmids\": [\n        \"32989246\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signal that designates nuclear SIRT1 for LC3 recognition not defined\",\n        \"Whether catalytic activity or modification state gates autophagic targeting unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened SIRT1's substrate range to hypoxia and selective autophagy, showing deacetylation of HIF-2\\u03b1 limits renal fibrosis and deacetylation of p62 (K295) blocks Keap1-mediated degradation to influence liver tumorigenesis.\",\n      \"evidence\": \"Co-IP, deacetylation and ubiquitination assays, conditional Sirt1 knockout mice, Hif2a epistasis, and DEN carcinogenesis with p62 rescue\",\n      \"pmids\": [\n        \"33758176\",\n        \"33854041\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"HIF-2\\u03b1 acetyl-lysine site not mapped\",\n        \"Context determining whether SIRT1 acts as tumor suppressor or promoter not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a phospho-acetyl switch on WEE1 controlled by SIRT1, showing CHK1-primed, GCN5-mediated K177 acetylation activates WEE1 while SIRT1 deacetylation maintains it inactive, with implications for WEE1-inhibitor resistance.\",\n      \"evidence\": \"Co-IP, in vitro deacetylation, K177 mutagenesis, kinase activity assays, and SIRT1 knockdown with WEE1-inhibitor sensitivity\",\n      \"pmids\": [\n        \"36635566\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance to tumor responses to WEE1 inhibition not established here\",\n        \"Interplay between SIRT1 control of CHK2 and WEE1 in the same checkpoint not integrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single deacetylase selects among its many competing substrates in a given cell state, and what determines whether deacetylation stabilizes or destabilizes a target, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model for substrate selection across metabolic, checkpoint, and immune contexts\",\n        \"Determinants of opposing stability outcomes (XRCC1/p62 stabilized vs p21/STAT3 destabilized) not defined\",\n        \"Quantitative coupling between NAD+/phosphorylation inputs and substrate-specific output not measured\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          2,\n          5,\n          6,\n          7,\n          9,\n          10,\n          11,\n          17,\n          18\n        ]\n      },\n      {\n        \"term_id\": \"GO:0016787\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          6,\n          7,\n          11\n        ]\n      },\n      {\n        \"term_id\": \"GO:0140110\",\n        \"supporting_discovery_ids\": [\n          15\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [\n          8,\n          15\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [\n          8\n        ]\n      },\n      {\n        \"term_id\": \"GO:0000228\",\n        \"supporting_discovery_ids\": [\n          15\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          13,\n          20\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1640170\",\n        \"supporting_discovery_ids\": [\n          3,\n          6,\n          11,\n          16,\n          18\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-73894\",\n        \"supporting_discovery_ids\": [\n          2,\n          7,\n          14\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [\n          5,\n          16\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-9612973\",\n        \"supporting_discovery_ids\": [\n          8,\n          10\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-74160\",\n        \"supporting_discovery_ids\": [\n          15,\n          19\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PPARGC1A\",\n      \"FOXO1\",\n      \"LXR\",\n      \"Ku70\",\n      \"CDK1\",\n      \"CHK2\",\n      \"WEE1\",\n      \"MAP1LC3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}