{"gene":"ACSS2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2017,"finding":"Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, which exposes its nuclear localization signal for importin α5 (KPNA1) binding and nuclear translocation. In the nucleus, ACSS2 binds transcription factor EB (TFEB) and localizes to lysosomal and autophagy gene promoters, where it recaptures acetate from histone deacetylation to locally produce acetyl-CoA for histone H3 acetylation, promoting lysosomal biogenesis and autophagy.","method":"AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2-importin α5, ACSS2-TFEB), ChIP, nuclear fractionation, knock-in of nuclear translocation-deficient mutants, cell survival and tumor growth assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (mutagenesis, Co-IP, ChIP, functional rescue) in a single rigorous study","pmids":["28552616","28820290"],"is_preprint":false},{"year":2024,"finding":"EGFR activation induces ERK-mediated phosphorylation of ACSS2 at S267, promoting its nuclear translocation and complex formation with KAT2A. ACSS2 functions as a lactyl-CoA synthetase, converting lactate to lactyl-CoA; a co-crystal structure shows lactyl-CoA binding to KAT2A, which then acts as a lactyltransferase to lactylate histone H3, driving expression of Wnt/β-catenin, NF-κB, and PD-L1.","method":"In vitro lactyl-CoA synthetase assay, co-crystal structure of KAT2A with lactyl-CoA, ERK phosphorylation assay, Co-IP (ACSS2-KAT2A), ChIP, interaction-blocking peptide, anti-PD-1 combination treatment in vivo","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structure, in vitro enzymatic assay, mutagenesis/peptide blocking, and in vivo validation in one study","pmids":["39561764"],"is_preprint":false},{"year":2015,"finding":"ACSS2 is required for CBP-mediated acetylation of HIF-2α during hypoxia and glucose deprivation; acetate levels rise during stress and ACSS2 supplies the acetyl-CoA needed for CBP/HIF-2α complex formation and HIF-2 transcriptional activation, linking nutrient sensing to stress signaling and tumor metastasis.","method":"ACSS2 knockdown/overexpression, acetate supplementation, HIF-2α acetylation assay, Co-IP (CBP/HIF-2α), colony formation/migration/invasion assays, mouse flank tumor model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional KD with defined phenotype, single lab","pmids":["25689462"],"is_preprint":false},{"year":2017,"finding":"ACSS2 promotes nuclear translocation in response to acetate/hypoxia/glucose deprivation, where it promotes acetylation of HIF-2α by CBP and regulates local histone 3 epigenetic marks; exogenous acetate augments ACSS2/HIF-2-dependent cancer growth and metastasis.","method":"Nuclear fractionation, acetate treatment, HIF-2α acetylation assay, Co-IP, mouse tumor model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (fractionation, Co-IP, in vivo), single lab, corroborates prior ACSS2/HIF-2 work","pmids":["29281714"],"is_preprint":false},{"year":2018,"finding":"ACSS2 expression generates crotonyl-CoA, which promotes histone crotonylation at the HIV LTR; ACSS2 induction reactivates latent HIV by reprogramming local chromatin through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminishes histone crotonylation-induced HIV reactivation.","method":"siRNA knockdown, ACSS2 pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assay (luciferase/viral outgrowth), SIV non-human primate model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, KD with defined chromatin and virological phenotype, in vivo SIV model; single lab","pmids":["29457784"],"is_preprint":false},{"year":2018,"finding":"ACSS2 deficiency in mice reduces dietary lipid absorption by the intestine and perturbs repartitioning of triglycerides from adipose to liver by lowering expression of lipid transporters and fatty acid oxidation genes, demonstrating that ACSS2 selectively regulates genes involved in lipid metabolism according to fed/fasted state.","method":"ACSS2 knockout mice, diet-induced obesity model, body weight/hepatic steatosis measurements, gene expression analysis of lipid metabolism genes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined metabolic phenotype and gene expression characterization, replicated across multiple dietary/physiological conditions","pmids":["30228117"],"is_preprint":false},{"year":2022,"finding":"OGT regulates acetate-dependent acetyl-CoA and lipid production in glioblastoma by controlling CDK5-dependent phosphorylation of ACSS2 at Ser-267, which reduces ACSS2 polyubiquitination and degradation, thereby stabilizing ACSS2 protein and increasing acetate-to-acetyl-CoA conversion.","method":"OGT overexpression/knockdown, CDK5 inhibition, phospho-site mutagenesis (Ser-267), ubiquitination assays, acetyl-CoA/lipid metabolic tracing, in vitro and in vivo GBM growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis, ubiquitination assay, metabolic tracing, and in vivo rescue in one study","pmids":["35190642"],"is_preprint":false},{"year":2021,"finding":"A transition-state mimetic small-molecule inhibitor of ACSS2 blocks its enzymatic activity (acetate-to-acetyl-CoA conversion) in vitro and in vivo, and pharmacologic inhibition as a single agent impairs breast tumor growth.","method":"In vitro ACSS2 enzymatic inhibition assay, transition-state mimetic synthesis, cell-based acetyl-CoA measurement, mouse breast tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic assay with defined inhibitor mechanism plus in vivo validation","pmids":["33414169"],"is_preprint":false},{"year":2024,"finding":"ACSS2 channels exogenous CAF-derived acetate to regulate the cancer epigenome; it mediates acetylation of SP1 at lysine 19, increasing SP1 protein stability and transcriptional activity, which drives SAT1 expression and alters polyamine homeostasis to promote pancreatic cancer survival in an acidic microenvironment.","method":"H3K27ac ChIP-seq, RNA-seq, Co-IP, mass spectrometry (SP1-K19ac identification), ACSS2 genetic/pharmacologic inhibition, mouse tumor models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — multi-omic ChIP-seq/RNA-seq, MS identification of acetylation site, Co-IP, and in vivo models in one study","pmids":["38429478"],"is_preprint":false},{"year":2024,"finding":"ACSS2 regulates de novo lipogenesis (DNL) in kidney tubular cells by producing acetyl-CoA from acetate, causing NADPH depletion and ROS elevation that activates NLRP3-dependent pyroptosis; ACSS2-KO mice are protected from kidney fibrosis in multiple disease models.","method":"ACSS2 knockout mice, primary tubular cell cultures, NADPH/ROS measurements, NLRP3 pathway analysis, fatty acid synthase inhibition, multiple fibrosis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — clean KO with mechanistic pathway dissection across multiple disease models","pmids":["38051585"],"is_preprint":false},{"year":2024,"finding":"ACSS2-produced crotonyl-CoA drives H3K9 crotonylation (H3K9cr) in tubular epithelial cells, and H3K9cr at the IL-1β locus upregulates IL-1β expression, promoting macrophage activation and tubular cell senescence in kidney fibrosis; genetic and pharmacologic ACSS2 inhibition suppresses H3K9cr-mediated IL-1β and delays renal fibrosis.","method":"ChIP-seq, RNA-seq, ACSS2 genetic knockdown and pharmacologic inhibition, H3K9cr/H3K9ac measurements, IL-1β expression, macrophage co-culture, fibrosis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq + RNA-seq integrated with genetic and pharmacologic perturbation and mechanistic pathway readouts","pmids":["38615014"],"is_preprint":false},{"year":2024,"finding":"ACSS2 directly interacts with and acetylates PAICS (a key purine biosynthesis enzyme) using locally produced acetyl-CoA; PAICS acetylation promotes its autophagy-mediated degradation, limiting purine metabolism and dNTP pools for DNA repair, thereby exacerbating cytoplasmic chromatin fragment accumulation and the senescence-associated secretory phenotype (SASP).","method":"Co-IP (ACSS2-PAICS), acetylation mass spectrometry, autophagy flux assays, dNTP pool measurements, Acss2 knockout mice, SASP cytokine profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP, MS identification of acetylation, functional KO with mechanistic dissection in vivo","pmids":["40021646"],"is_preprint":false},{"year":2024,"finding":"ACSS2 controls PPARγ activity homeostasis by binding directly to acetylated PPARγ in the presence of ligand and recruiting SIRT1 and PRDM16 to activate UCP1 expression; SIRT1 then deacetylates PPARγ and triggers ACSS2 translocation to P300, inducing PPARγ polyubiquitination and degradation, thereby coupling PPARγ activation with degradation to enhance adipose plasticity.","method":"Co-IP (ACSS2-PPARγ, ACSS2-SIRT1, ACSS2-PRDM16), acetylation/ubiquitination assays, ACSS2 KO mice, UCP1 reporter, high-fat diet model with D-mannose treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and defined functional readouts, single lab","pmids":["38332049"],"is_preprint":false},{"year":2024,"finding":"ACSS2 inhibition reduces chromatin accessibility and HIF-2α expression and stability in clear cell renal cell carcinoma; mechanistically, loss of ACSS2 promotes HIF-2α degradation via a pVHL-independent pathway involving the E3 ligase MUL1, which directly interacts with HIF-2α.","method":"ACSS2 inhibition, ATAC-seq (chromatin accessibility), HIF-2α protein stability assays, Co-IP (MUL1-HIF-2α), MUL1 overexpression, primary patient tumor cultures, in vivo ccRCC models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — ATAC-seq, Co-IP, and functional in vivo/ex vivo data; single lab","pmids":["38941296"],"is_preprint":false},{"year":2024,"finding":"ACSS2 is unable to generate butyryl-CoA or crotonyl-CoA from butyrate or crotonate in direct in vitro enzymatic assays with purified/recombinant enzyme, demonstrating its substrate specificity is restricted to acetate for acetyl-CoA production.","method":"In vitro enzymatic assay with purified recombinant ACSS2, structural analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro reconstitution assay with purified enzyme and structural validation","pmids":["38369012"],"is_preprint":false},{"year":2024,"finding":"In CD8 T cells, when ACLY (the primary cytosolic acetyl-CoA source from citrate) is ablated, ACSS2 mediates an alternative acetate-dependent pathway for acetyl-CoA production that maintains TCA cycle fueling, histone acetylation, and chromatin accessibility at effector gene loci to sustain T cell effector function in vivo.","method":"ACLY KO, ACSS2 KO (single and double), stable isotope (13C-acetate) tracing, ATAC-seq, histone acetylation assays, in vivo infection models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — isotope tracing, ATAC-seq, double KO epistasis, and in vivo functional validation in one study","pmids":["39150482"],"is_preprint":false},{"year":2023,"finding":"ACSS2 upregulation in Alzheimer's disease mouse hippocampus restores H3K9ac and H4K12ac enrichment at NMDAR and AMPAR gene promoters, increasing receptor expression and rescuing synaptic plasticity and cognitive function; acetate replenishment achieves the same effect in an ACSS2-dependent manner.","method":"AAV-mediated ACSS2 overexpression in dorsal hippocampus, ChIP-qPCR (H3K9ac, H4K12ac at NMDAR/AMPAR promoters), RNA-seq, electrophysiology (LTP), Morris water maze","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-qPCR, electrophysiology, and behavioral rescue with ACSS2 as mechanistic node; single lab","pmids":["37438762"],"is_preprint":false},{"year":2023,"finding":"ACSS2 mediates NF-κB-dependent downregulation of CA9 in pancreatic cancer cells during alkaliptosis by producing acetyl-CoA that supports histone acetylation; this contributes to intracellular pH decrease and pH-dependent cell death.","method":"ACSS2 shRNA knockdown, western blot/qPCR, intracellular pH measurement, histone acetylation assay, HDAC inhibitor (TSA) combined treatment","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic follow-up, no direct ChIP or Co-IP","pmids":["36707625"],"is_preprint":false},{"year":2023,"finding":"Alcohol metabolism generates acetate that promotes ACSS2 nuclear import; nuclear ACSS2 recruits PCAF acetyltransferase to mediate H3K9 acetylation at Fasn and Acaca promoters, driving lipogenic gene expression and hepatic steatosis.","method":"Liver-specific ACSS2 knockdown mice, CUT&RUN (H3K9ac at Fasn/Acaca promoters), Co-IP (PCAF-H3K9), nuclear fractionation, ethanol feeding model","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 — CUT&RUN, Co-IP, liver-specific KD with defined chromatin phenotype; single lab","pmids":["37183518"],"is_preprint":false},{"year":2025,"finding":"ACSS2 binds CBP to mediate histone acetylation and regulate hepcidin (HAMP1/2) transcription; ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and hepatocyte ferroptosis in alcoholic liver disease.","method":"ACSS2 KO/overexpression, Co-IP (ACSS2-CBP), histone acetylation at HAMP1/2 promoters, iron metabolism measurements, ferroptosis assays, HAMP1/2 rescue overexpression","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, chromatin acetylation at defined promoters, rescue experiments; single lab","pmids":["40593779"],"is_preprint":false},{"year":2020,"finding":"NRF2 transcriptionally upregulates ACSS2 in esophageal squamous cell carcinoma cells; ACSS2 converts ethanol-derived acetate to acetyl-CoA, increasing ATP levels and driving lipid synthesis and invasive capability in NRF2-high cells exposed to ethanol.","method":"NRF2/ACSS2 siRNA knockdown, acetyl-CoA/ATP metabolic measurements, lipid synthesis assays, invasion assays, ethanol exposure","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with metabolic and functional readouts; single lab","pmids":["32776152"],"is_preprint":false},{"year":2017,"finding":"SREBP-1 directly regulates ACSS2 transcription by binding an SRE element at −475 to −483 bp on the ACSS2 promoter as demonstrated by luciferase reporter and ChIP assay; simultaneous knockdown of ACSS2 and ACLY reduces de novo fatty acid synthesis, TAG synthesis, and lipid droplet formation in mammary epithelial cells.","method":"Luciferase reporter assay, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, TAG content measurement, lipid droplet staining","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay and ChIP for promoter regulation, KD with metabolic phenotype; single lab","pmids":["28407230"],"is_preprint":false},{"year":2019,"finding":"Alternative transcription start site selection in ACSS2 generates two isoforms (ACSS2-S1 and ACSS2-S2) with different subcellular localizations: ACSS2-S1 is cytoplasmic, while ACSS2-S2 distributes in both nucleus and cytoplasm. ACSS2-S2 overexpression promotes cell proliferation, invasion, and ribosome biogenesis in hepatocellular carcinoma, whereas ACSS2-S1 does not.","method":"Transcription start site sequencing, subcellular fractionation/immunofluorescence, isoform-specific overexpression, proliferation/invasion assays, ribosome biogenesis analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single lab, isoform localization with functional readout but limited mechanistic depth","pmids":["31076106"],"is_preprint":false},{"year":2024,"finding":"ACSS2 interacts with HMGCS1 (by Co-IP) to regulate lipid metabolism reprogramming and the PI3K/AKT/mTOR pathway in pancreatic neuroendocrine neoplasms; HMGCS1 overexpression reverses the lipogenic and pro-tumorigenic effects of ACSS2 knockdown.","method":"Co-IP (ACSS2-HMGCS1), CCK-8/colony formation/EdU proliferation assays, transwell invasion, nude mouse xenografts, PI3K/AKT/mTOR pathway analysis","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with functional rescue; single lab, limited mechanistic detail","pmids":["38263056"],"is_preprint":false},{"year":2024,"finding":"SCAP N-glycosylation increases both SREBP-1-mediated ACSS2 transcription and AMPK-mediated S659 phosphorylation of ACSS2, promoting nuclear ACSS2 accumulation and H3K27 acetylation, which drives lipogenic gene expression and hepatic inflammation in NASH.","method":"SCAP N-glycosylation site mutagenesis, ACSS2 expression/localization assays, AMPK phosphorylation assay, H3K27ac measurements, lipid accumulation assays in hepatic cell lines","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis, defined phosphorylation event, chromatin acetylation, and functional phenotype; single lab","pmids":["38591127"],"is_preprint":false},{"year":2024,"finding":"ACSS2 promotes neuronal TPH2 transcription by binding PPARγ as a co-activator and supporting histone acetylation at the TPH2 promoter; ACSS2 is required for SCFA-mediated antidepressant responses, and PPARγ is identified as a novel ACSS2 partner for activating CRTC1 transcription.","method":"Stereotaxic AAV-mediated neuronal ACSS2 knockdown, Co-IP/interaction assay (ACSS2-PPARγ), ChIP (histone acetylation at TPH2/CRTC1 promoters), behavioral tests (chronic-restraint-stress model)","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, in vivo KD with behavioral phenotype; single lab","pmids":["38939042"],"is_preprint":false}],"current_model":"ACSS2 is a nucleocytosolic enzyme that converts acetate (and, under specific signaling contexts, lactate) to acetyl-CoA or lactyl-CoA; it is regulated by AMPK-mediated S659 phosphorylation (promoting nuclear translocation under nutrient stress), ERK-mediated S267 phosphorylation (promoting nuclear translocation downstream of EGFR), and CDK5-mediated S267 phosphorylation (stabilizing ACSS2 protein via reduced ubiquitination); in the nucleus, ACSS2 associates with TFEB, KAT2A, CBP, PCAF, and PPARγ to locally regenerate acetyl-CoA from histone deacetylation-derived acetate for targeted histone acetylation at gene promoters governing lysosomal biogenesis, autophagy, lipogenesis, immune evasion, and stress responses, while its cytosolic pool supports de novo lipogenesis, fatty acid synthesis, and metabolic acetyl-CoA supply for diverse cellular processes."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that ACSS2 links nutrient stress to transcription factor acetylation: it was unknown how acetyl-CoA was supplied for CBP-mediated HIF-2α acetylation under hypoxia/glucose deprivation; experiments showed ACSS2 is required to convert stress-elevated acetate into acetyl-CoA for CBP/HIF-2α complex formation, connecting metabolic stress sensing to HIF-2 transcriptional activation.","evidence":"ACSS2 knockdown/overexpression with HIF-2α acetylation assays, Co-IP, and mouse tumor models","pmids":["25689462"],"confidence":"Medium","gaps":["Single lab; no ChIP to demonstrate chromatin-level mechanism","Direct ACSS2-CBP physical interaction not resolved at this stage","Whether ACSS2 nuclear entry is regulated was not addressed"]},{"year":2017,"claim":"Defining the AMPK–ACSS2 nuclear translocation axis and chromatin-level recycling mechanism: it was unknown how ACSS2 entered the nucleus or how acetyl-CoA was locally supplied at gene promoters; this work showed AMPK phosphorylates ACSS2 at S659, exposing an NLS for importin-α5 binding, and that nuclear ACSS2 binds TFEB at autophagy/lysosomal gene promoters to recapture histone deacetylation-derived acetate for local acetyl-CoA regeneration and histone H3 acetylation.","evidence":"AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2–importin-α5, ACSS2–TFEB), ChIP, nuclear fractionation, knock-in mutants, tumor growth assays","pmids":["28552616","28820290"],"confidence":"High","gaps":["Whether other kinases also regulate ACSS2 nuclear entry was unresolved","Structural basis of acetate recycling at chromatin not determined","Generality beyond lysosomal/autophagy genes unknown"]},{"year":2017,"claim":"Identifying transcriptional regulation of ACSS2 by SREBP-1 and its role in de novo lipogenesis: it was unclear how ACSS2 expression itself was controlled; SREBP-1 was shown to directly bind the ACSS2 promoter SRE, and combined ACSS2/ACLY depletion abolished fatty acid and TAG synthesis.","evidence":"Luciferase reporter, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, lipid measurements","pmids":["28407230"],"confidence":"Medium","gaps":["Only tested in mammary epithelial cells","Post-translational regulation of ACSS2 protein levels not addressed"]},{"year":2018,"claim":"Extending ACSS2's chromatin role to non-acetyl acyl modifications and viral latency: it was unknown whether ACSS2 could drive histone crotonylation; ACSS2 was shown to generate crotonyl-CoA that promotes histone crotonylation at the HIV LTR, reactivating latent provirus.","evidence":"siRNA knockdown, pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assays, SIV primate model","pmids":["29457784"],"confidence":"Medium","gaps":["Direct in vitro crotonyl-CoA synthetase activity of purified ACSS2 was not reconstituted","Whether acetate or crotonate is the physiological substrate for crotonylation was unclear"]},{"year":2018,"claim":"Demonstrating ACSS2's whole-organism role in lipid metabolism: it was unknown whether ACSS2 loss would affect systemic lipid handling; ACSS2 knockout mice showed reduced intestinal lipid absorption and altered triglyceride repartitioning between adipose and liver in a fed/fasted state-dependent manner.","evidence":"ACSS2 knockout mice, diet-induced obesity model, gene expression profiling","pmids":["30228117"],"confidence":"High","gaps":["Nuclear versus cytosolic contribution to the metabolic phenotype not dissected","Compensatory changes in ACLY or other acetyl-CoA sources not fully characterized"]},{"year":2022,"claim":"Revealing CDK5-mediated post-translational stabilization of ACSS2: it was unclear how ACSS2 protein levels were regulated; OGT-dependent CDK5 phosphorylation of ACSS2 at S267 was shown to reduce polyubiquitination and degradation, stabilizing ACSS2 and increasing acetyl-CoA and lipid production in glioblastoma.","evidence":"Phospho-site mutagenesis (S267), ubiquitination assays, metabolic tracing, in vivo GBM growth","pmids":["35190642"],"confidence":"High","gaps":["Whether S267 phosphorylation also affects nuclear translocation (as later shown for ERK) was not tested","Identity of the E3 ligase mediating ACSS2 ubiquitination was not determined"]},{"year":2023,"claim":"Demonstrating ACSS2's nuclear role in alcohol-induced hepatic lipogenesis: it was unknown how ethanol-derived acetate reprograms lipogenic chromatin; nuclear ACSS2 was shown to recruit PCAF acetyltransferase for H3K9 acetylation at Fasn and Acaca promoters, driving hepatic steatosis.","evidence":"Liver-specific ACSS2 knockdown mice, CUT&RUN, Co-IP (PCAF–H3K9), ethanol feeding model","pmids":["37183518"],"confidence":"Medium","gaps":["Whether ACSS2 directly binds PCAF or acts via intermediate complex not resolved","Contribution relative to ACLY in this context not quantified"]},{"year":2023,"claim":"Extending ACSS2's chromatin function to neuronal gene regulation: it was unknown whether ACSS2-dependent histone acetylation controlled synaptic receptor expression; hippocampal ACSS2 overexpression restored H3K9ac and H4K12ac at NMDAR/AMPAR promoters, rescuing synaptic plasticity and cognition in Alzheimer's disease mice.","evidence":"AAV-mediated ACSS2 overexpression, ChIP-qPCR, electrophysiology, Morris water maze","pmids":["37438762"],"confidence":"Medium","gaps":["Overexpression-based; loss-of-function confirmation in neurodegeneration models lacking","Whether acetate availability is limiting in AD brain not established"]},{"year":2024,"claim":"Discovering ACSS2 as a lactyl-CoA synthetase and defining the EGFR–ERK–ACSS2–KAT2A histone lactylation axis: it was unknown how histone lactylation substrates were generated; ACSS2 was shown to convert lactate to lactyl-CoA downstream of ERK-mediated S267 phosphorylation, and a co-crystal structure revealed lactyl-CoA binding to KAT2A, which then lactylates histone H3 to drive PD-L1 and Wnt/NF-κB expression.","evidence":"In vitro lactyl-CoA synthetase assay, co-crystal structure (KAT2A–lactyl-CoA), ERK phosphorylation assay, Co-IP, ChIP, in vivo anti-PD-1 combination","pmids":["39561764"],"confidence":"High","gaps":["Contradicts the 2024 finding that purified ACSS2 cannot use butyrate/crotonate—substrate specificity boundaries for short-chain acids need reconciliation","Whether lactyl-CoA synthesis is kinetically relevant at physiological lactate concentrations in vivo is unresolved"]},{"year":2024,"claim":"Clarifying ACSS2 substrate specificity: it was debated whether ACSS2 could generate crotonyl-CoA or butyryl-CoA; purified recombinant ACSS2 was shown to be unable to use butyrate or crotonate as substrates, restricting its primary activity to acetate-to-acetyl-CoA conversion.","evidence":"In vitro enzymatic assay with purified recombinant ACSS2, structural analysis","pmids":["38369012"],"confidence":"High","gaps":["Does not address the lactyl-CoA synthetase activity reported separately","Cell-based crotonylation attributed to ACSS2 in prior studies remains mechanistically unexplained"]},{"year":2024,"claim":"Demonstrating ACSS2-mediated non-histone substrate acetylation: it was unknown whether ACSS2 directly acetylated non-histone proteins; ACSS2 was shown to acetylate SP1 at K19 (stabilizing SP1 for SAT1-driven polyamine reprogramming) and PAICS (promoting its autophagic degradation to limit purine biosynthesis and dNTP pools, exacerbating senescence-associated phenotypes).","evidence":"Co-IP, acetylation mass spectrometry, autophagy flux assays, dNTP measurements, ACSS2 KO mice, SASP profiling; ChIP-seq/RNA-seq for SP1/SAT1 axis in pancreatic cancer models","pmids":["38429478","40021646"],"confidence":"High","gaps":["Whether ACSS2 itself has intrinsic acetyltransferase activity or channels acetyl-CoA to an acetyltransferase for these substrates is not fully distinguished","Range of non-histone substrates likely incomplete"]},{"year":2024,"claim":"Establishing ACSS2 as a compensatory acetyl-CoA source maintaining T cell effector chromatin: it was unknown whether ACSS2 could sustain epigenetic and metabolic programs when the primary ACLY pathway was absent; double-KO epistasis with 13C-acetate tracing showed ACSS2 maintains TCA fueling, histone acetylation, and chromatin accessibility at effector gene loci in CD8 T cells.","evidence":"ACLY KO, ACSS2 KO, double KO, 13C-acetate tracing, ATAC-seq, in vivo infection models","pmids":["39150482"],"confidence":"High","gaps":["Relative contribution of ACSS2 versus ACLY under normal (non-KO) physiological conditions not quantified","Whether this compensation operates in other immune cell types untested"]},{"year":2024,"claim":"Linking ACSS2-driven lipogenesis to NLRP3 pyroptosis and kidney fibrosis: it was unknown how acetate metabolism caused tubular injury; ACSS2-produced acetyl-CoA was shown to drive de novo lipogenesis that depletes NADPH and elevates ROS, activating NLRP3-dependent pyroptosis; separately, ACSS2-produced crotonyl-CoA drives H3K9 crotonylation at the IL-1β locus, amplifying inflammation.","evidence":"ACSS2 KO mice, primary tubular cells, NADPH/ROS measurements, NLRP3 pathway, ChIP-seq/RNA-seq for H3K9cr, multiple fibrosis models","pmids":["38051585","38615014"],"confidence":"High","gaps":["How ACSS2 generates crotonyl-CoA given its inability to use crotonate in vitro is mechanistically unexplained","Relative importance of lipogenesis-ROS versus H3K9cr-IL-1β arms not resolved"]},{"year":2024,"claim":"Defining ACSS2 as a PPARγ co-activator coupling activation to degradation in adipose plasticity: it was unknown how PPARγ activity was homeostatically regulated; ACSS2 was shown to bind acetylated PPARγ, recruit SIRT1 and PRDM16 for UCP1 activation, then facilitate PPARγ polyubiquitination and degradation via P300.","evidence":"Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), ubiquitination assays, ACSS2 KO mice, high-fat diet model","pmids":["38332049"],"confidence":"Medium","gaps":["Sequential model (activation then degradation) not validated by real-time dynamics","Structural basis of ACSS2–PPARγ interaction not determined"]},{"year":2025,"claim":"Connecting ACSS2–CBP to iron homeostasis regulation: it was unknown how acetyl-CoA metabolism influenced hepcidin transcription; ACSS2 was shown to bind CBP and maintain histone acetylation at HAMP1/2 promoters, with ACSS2 deficiency causing hepcidin downregulation, systemic iron dyshomeostasis, and hepatocyte ferroptosis in alcoholic liver disease.","evidence":"ACSS2 KO/overexpression, Co-IP (ACSS2–CBP), histone acetylation at HAMP promoters, iron metabolism and ferroptosis assays, rescue experiments","pmids":["40593779"],"confidence":"Medium","gaps":["Whether the iron phenotype is direct or secondary to broader chromatin accessibility changes not resolved","Single lab, not independently replicated"]},{"year":null,"claim":"Key unresolved questions include: (1) how ACSS2 generates crotonyl-CoA and lactyl-CoA in cells given its in vitro restriction to acetate; (2) whether ACSS2 possesses intrinsic protein acetyltransferase activity or solely channels acetyl-CoA to partner acetyltransferases; (3) the structural basis of ACSS2's association with diverse transcription factor and acetyltransferase partners; and (4) the relative quantitative contributions of ACSS2 versus ACLY to chromatin acetylation under physiological (non-KO) conditions in different tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length ACSS2 in complex with nuclear partners","No kinetic comparison of ACSS2 lactyl-CoA vs acetyl-CoA synthetase activity under physiological substrate concentrations","Tissue-specific isoform functions (ACSS2-S1 vs ACSS2-S2) remain poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,7,14,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,12,25]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4,10,16,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3,8,16,18,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,9,15,21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,4,8,10,16,18,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,7,9,15,20,21]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,18,19,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,13]}],"complexes":[],"partners":["TFEB","KAT2A","CBP","PCAF","PPARΓ","SP1","PAICS","SIRT1"],"other_free_text":[]},"mechanistic_narrative":"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate to acetyl-CoA (and lactate to lactyl-CoA) to fuel both metabolic and epigenetic programs across diverse cell types. In the cytosol, ACSS2-generated acetyl-CoA supports de novo lipogenesis, fatty acid synthesis, and TCA cycle anaplerosis, serving as an essential alternative to ACLY-derived acetyl-CoA when citrate-dependent pathways are compromised [PMID:15, PMID:30228117, PMID:28407230]. Signal-dependent phosphorylation—AMPK at S659 under glucose deprivation or ERK/CDK5 at S267 downstream of EGFR or OGT signaling—drives nuclear translocation, where ACSS2 associates with transcription factors (TFEB, PPARγ, SP1) and acetyltransferases (CBP, KAT2A, PCAF) to locally regenerate acetyl-CoA from deacetylation-released acetate, thereby sustaining targeted histone acetylation, crotonylation, and lactylation at promoters governing autophagy, lysosomal biogenesis, lipogenesis, immune evasion, and stress responses [PMID:28552616, PMID:39561764, PMID:35190642, PMID:38429478, PMID:37183518]. ACSS2 also directly acetylates non-histone substrates—SP1 (K19) to stabilize it and PAICS to promote its autophagic degradation—thereby extending its regulatory reach beyond chromatin to transcription factor stability and purine metabolism [PMID:38429478, PMID:40021646]."},"prefetch_data":{"uniprot":{"accession":"Q9NR19","full_name":"Acetyl-coenzyme A synthetase, cytoplasmic","aliases":["Acetate--CoA ligase","Acetyl-CoA synthetase","ACS","AceCS","Acetyl-CoA synthetase 1","AceCS1","Acyl-CoA synthetase short-chain family member 2","Acyl-activating enzyme","Propionate--CoA ligase"],"length_aa":701,"mass_kda":78.6,"function":"Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:10843999, PubMed:28003429, PubMed:28552616). Acetate is the preferred substrate (PubMed:10843999, PubMed:28003429). Can also utilize propionate with a much lower affinity (By similarity). Nuclear ACSS2 promotes glucose deprivation-induced lysosomal biogenesis and autophagy, tumor cell survival and brain tumorigenesis (PubMed:28552616). Glucose deprivation results in AMPK-mediated phosphorylation of ACSS2 leading to its translocation to the nucleus where it binds to TFEB and locally produces acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes thereby activating their transcription (PubMed:28552616). The regulation of genes associated with autophagy and lysosomal activity through ACSS2 is important for brain tumorigenesis and tumor survival (PubMed:28552616). Acts as a chromatin-bound transcriptional coactivator that up-regulates histone acetylation and expression of neuronal genes (By similarity). Can be recruited to the loci of memory-related neuronal genes to maintain a local acetyl-CoA pool, providing the substrate for histone acetylation and promoting the expression of specific genes, which is essential for maintaining long-term spatial memory (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NR19/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACSS2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACSS2","total_profiled":1310},"omim":[{"mim_id":"614355","title":"ACYL-CoA SYNTHETASE SHORT CHAIN FAMILY, MEMBER 1; ACSS1","url":"https://www.omim.org/entry/614355"},{"mim_id":"605832","title":"ACETYL-CoA SYNTHETASE SHORT CHAIN FAMILY, MEMBER 2; ACSS2","url":"https://www.omim.org/entry/605832"},{"mim_id":"108728","title":"ATP CITRATE LYASE; ACLY","url":"https://www.omim.org/entry/108728"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":109.9}],"url":"https://www.proteinatlas.org/search/ACSS2"},"hgnc":{"alias_symbol":["ACS","ACSA","AceCS","dJ1161H23.1"],"prev_symbol":["ACAS2"]},"alphafold":{"accession":"Q9NR19","domains":[{"cath_id":"3.40.50.12780","chopping":"45-255_282-556","consensus_level":"medium","plddt":95.2391,"start":45,"end":556},{"cath_id":"3.30.300.30","chopping":"576-696","consensus_level":"high","plddt":87.1754,"start":576,"end":696}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR19","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR19-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR19-F1-predicted_aligned_error_v6.png","plddt_mean":89.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACSS2","jax_strain_url":"https://www.jax.org/strain/search?query=ACSS2"},"sequence":{"accession":"Q9NR19","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR19.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR19/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR19"}},"corpus_meta":[{"pmid":"28552616","id":"PMC_28552616","title":"Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28552616","citation_count":287,"is_preprint":false},{"pmid":"39561764","id":"PMC_39561764","title":"ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion.","date":"2024","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39561764","citation_count":168,"is_preprint":false},{"pmid":"15949763","id":"PMC_15949763","title":"Eto Brute? 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In the nucleus, ACSS2 binds transcription factor EB (TFEB) and localizes to lysosomal and autophagy gene promoters, where it recaptures acetate from histone deacetylation to locally produce acetyl-CoA for histone H3 acetylation, promoting lysosomal biogenesis and autophagy.\",\n      \"method\": \"AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2-importin α5, ACSS2-TFEB), ChIP, nuclear fractionation, knock-in of nuclear translocation-deficient mutants, cell survival and tumor growth assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (mutagenesis, Co-IP, ChIP, functional rescue) in a single rigorous study\",\n      \"pmids\": [\"28552616\", \"28820290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGFR activation induces ERK-mediated phosphorylation of ACSS2 at S267, promoting its nuclear translocation and complex formation with KAT2A. ACSS2 functions as a lactyl-CoA synthetase, converting lactate to lactyl-CoA; a co-crystal structure shows lactyl-CoA binding to KAT2A, which then acts as a lactyltransferase to lactylate histone H3, driving expression of Wnt/β-catenin, NF-κB, and PD-L1.\",\n      \"method\": \"In vitro lactyl-CoA synthetase assay, co-crystal structure of KAT2A with lactyl-CoA, ERK phosphorylation assay, Co-IP (ACSS2-KAT2A), ChIP, interaction-blocking peptide, anti-PD-1 combination treatment in vivo\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure, in vitro enzymatic assay, mutagenesis/peptide blocking, and in vivo validation in one study\",\n      \"pmids\": [\"39561764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ACSS2 is required for CBP-mediated acetylation of HIF-2α during hypoxia and glucose deprivation; acetate levels rise during stress and ACSS2 supplies the acetyl-CoA needed for CBP/HIF-2α complex formation and HIF-2 transcriptional activation, linking nutrient sensing to stress signaling and tumor metastasis.\",\n      \"method\": \"ACSS2 knockdown/overexpression, acetate supplementation, HIF-2α acetylation assay, Co-IP (CBP/HIF-2α), colony formation/migration/invasion assays, mouse flank tumor model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional KD with defined phenotype, single lab\",\n      \"pmids\": [\"25689462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ACSS2 promotes nuclear translocation in response to acetate/hypoxia/glucose deprivation, where it promotes acetylation of HIF-2α by CBP and regulates local histone 3 epigenetic marks; exogenous acetate augments ACSS2/HIF-2-dependent cancer growth and metastasis.\",\n      \"method\": \"Nuclear fractionation, acetate treatment, HIF-2α acetylation assay, Co-IP, mouse tumor model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (fractionation, Co-IP, in vivo), single lab, corroborates prior ACSS2/HIF-2 work\",\n      \"pmids\": [\"29281714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACSS2 expression generates crotonyl-CoA, which promotes histone crotonylation at the HIV LTR; ACSS2 induction reactivates latent HIV by reprogramming local chromatin through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminishes histone crotonylation-induced HIV reactivation.\",\n      \"method\": \"siRNA knockdown, ACSS2 pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assay (luciferase/viral outgrowth), SIV non-human primate model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, KD with defined chromatin and virological phenotype, in vivo SIV model; single lab\",\n      \"pmids\": [\"29457784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACSS2 deficiency in mice reduces dietary lipid absorption by the intestine and perturbs repartitioning of triglycerides from adipose to liver by lowering expression of lipid transporters and fatty acid oxidation genes, demonstrating that ACSS2 selectively regulates genes involved in lipid metabolism according to fed/fasted state.\",\n      \"method\": \"ACSS2 knockout mice, diet-induced obesity model, body weight/hepatic steatosis measurements, gene expression analysis of lipid metabolism genes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic phenotype and gene expression characterization, replicated across multiple dietary/physiological conditions\",\n      \"pmids\": [\"30228117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OGT regulates acetate-dependent acetyl-CoA and lipid production in glioblastoma by controlling CDK5-dependent phosphorylation of ACSS2 at Ser-267, which reduces ACSS2 polyubiquitination and degradation, thereby stabilizing ACSS2 protein and increasing acetate-to-acetyl-CoA conversion.\",\n      \"method\": \"OGT overexpression/knockdown, CDK5 inhibition, phospho-site mutagenesis (Ser-267), ubiquitination assays, acetyl-CoA/lipid metabolic tracing, in vitro and in vivo GBM growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis, ubiquitination assay, metabolic tracing, and in vivo rescue in one study\",\n      \"pmids\": [\"35190642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A transition-state mimetic small-molecule inhibitor of ACSS2 blocks its enzymatic activity (acetate-to-acetyl-CoA conversion) in vitro and in vivo, and pharmacologic inhibition as a single agent impairs breast tumor growth.\",\n      \"method\": \"In vitro ACSS2 enzymatic inhibition assay, transition-state mimetic synthesis, cell-based acetyl-CoA measurement, mouse breast tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay with defined inhibitor mechanism plus in vivo validation\",\n      \"pmids\": [\"33414169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 channels exogenous CAF-derived acetate to regulate the cancer epigenome; it mediates acetylation of SP1 at lysine 19, increasing SP1 protein stability and transcriptional activity, which drives SAT1 expression and alters polyamine homeostasis to promote pancreatic cancer survival in an acidic microenvironment.\",\n      \"method\": \"H3K27ac ChIP-seq, RNA-seq, Co-IP, mass spectrometry (SP1-K19ac identification), ACSS2 genetic/pharmacologic inhibition, mouse tumor models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multi-omic ChIP-seq/RNA-seq, MS identification of acetylation site, Co-IP, and in vivo models in one study\",\n      \"pmids\": [\"38429478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 regulates de novo lipogenesis (DNL) in kidney tubular cells by producing acetyl-CoA from acetate, causing NADPH depletion and ROS elevation that activates NLRP3-dependent pyroptosis; ACSS2-KO mice are protected from kidney fibrosis in multiple disease models.\",\n      \"method\": \"ACSS2 knockout mice, primary tubular cell cultures, NADPH/ROS measurements, NLRP3 pathway analysis, fatty acid synthase inhibition, multiple fibrosis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with mechanistic pathway dissection across multiple disease models\",\n      \"pmids\": [\"38051585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2-produced crotonyl-CoA drives H3K9 crotonylation (H3K9cr) in tubular epithelial cells, and H3K9cr at the IL-1β locus upregulates IL-1β expression, promoting macrophage activation and tubular cell senescence in kidney fibrosis; genetic and pharmacologic ACSS2 inhibition suppresses H3K9cr-mediated IL-1β and delays renal fibrosis.\",\n      \"method\": \"ChIP-seq, RNA-seq, ACSS2 genetic knockdown and pharmacologic inhibition, H3K9cr/H3K9ac measurements, IL-1β expression, macrophage co-culture, fibrosis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq + RNA-seq integrated with genetic and pharmacologic perturbation and mechanistic pathway readouts\",\n      \"pmids\": [\"38615014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 directly interacts with and acetylates PAICS (a key purine biosynthesis enzyme) using locally produced acetyl-CoA; PAICS acetylation promotes its autophagy-mediated degradation, limiting purine metabolism and dNTP pools for DNA repair, thereby exacerbating cytoplasmic chromatin fragment accumulation and the senescence-associated secretory phenotype (SASP).\",\n      \"method\": \"Co-IP (ACSS2-PAICS), acetylation mass spectrometry, autophagy flux assays, dNTP pool measurements, Acss2 knockout mice, SASP cytokine profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP, MS identification of acetylation, functional KO with mechanistic dissection in vivo\",\n      \"pmids\": [\"40021646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 controls PPARγ activity homeostasis by binding directly to acetylated PPARγ in the presence of ligand and recruiting SIRT1 and PRDM16 to activate UCP1 expression; SIRT1 then deacetylates PPARγ and triggers ACSS2 translocation to P300, inducing PPARγ polyubiquitination and degradation, thereby coupling PPARγ activation with degradation to enhance adipose plasticity.\",\n      \"method\": \"Co-IP (ACSS2-PPARγ, ACSS2-SIRT1, ACSS2-PRDM16), acetylation/ubiquitination assays, ACSS2 KO mice, UCP1 reporter, high-fat diet model with D-mannose treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and defined functional readouts, single lab\",\n      \"pmids\": [\"38332049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 inhibition reduces chromatin accessibility and HIF-2α expression and stability in clear cell renal cell carcinoma; mechanistically, loss of ACSS2 promotes HIF-2α degradation via a pVHL-independent pathway involving the E3 ligase MUL1, which directly interacts with HIF-2α.\",\n      \"method\": \"ACSS2 inhibition, ATAC-seq (chromatin accessibility), HIF-2α protein stability assays, Co-IP (MUL1-HIF-2α), MUL1 overexpression, primary patient tumor cultures, in vivo ccRCC models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ATAC-seq, Co-IP, and functional in vivo/ex vivo data; single lab\",\n      \"pmids\": [\"38941296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 is unable to generate butyryl-CoA or crotonyl-CoA from butyrate or crotonate in direct in vitro enzymatic assays with purified/recombinant enzyme, demonstrating its substrate specificity is restricted to acetate for acetyl-CoA production.\",\n      \"method\": \"In vitro enzymatic assay with purified recombinant ACSS2, structural analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro reconstitution assay with purified enzyme and structural validation\",\n      \"pmids\": [\"38369012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In CD8 T cells, when ACLY (the primary cytosolic acetyl-CoA source from citrate) is ablated, ACSS2 mediates an alternative acetate-dependent pathway for acetyl-CoA production that maintains TCA cycle fueling, histone acetylation, and chromatin accessibility at effector gene loci to sustain T cell effector function in vivo.\",\n      \"method\": \"ACLY KO, ACSS2 KO (single and double), stable isotope (13C-acetate) tracing, ATAC-seq, histone acetylation assays, in vivo infection models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — isotope tracing, ATAC-seq, double KO epistasis, and in vivo functional validation in one study\",\n      \"pmids\": [\"39150482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSS2 upregulation in Alzheimer's disease mouse hippocampus restores H3K9ac and H4K12ac enrichment at NMDAR and AMPAR gene promoters, increasing receptor expression and rescuing synaptic plasticity and cognitive function; acetate replenishment achieves the same effect in an ACSS2-dependent manner.\",\n      \"method\": \"AAV-mediated ACSS2 overexpression in dorsal hippocampus, ChIP-qPCR (H3K9ac, H4K12ac at NMDAR/AMPAR promoters), RNA-seq, electrophysiology (LTP), Morris water maze\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-qPCR, electrophysiology, and behavioral rescue with ACSS2 as mechanistic node; single lab\",\n      \"pmids\": [\"37438762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSS2 mediates NF-κB-dependent downregulation of CA9 in pancreatic cancer cells during alkaliptosis by producing acetyl-CoA that supports histone acetylation; this contributes to intracellular pH decrease and pH-dependent cell death.\",\n      \"method\": \"ACSS2 shRNA knockdown, western blot/qPCR, intracellular pH measurement, histone acetylation assay, HDAC inhibitor (TSA) combined treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic follow-up, no direct ChIP or Co-IP\",\n      \"pmids\": [\"36707625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alcohol metabolism generates acetate that promotes ACSS2 nuclear import; nuclear ACSS2 recruits PCAF acetyltransferase to mediate H3K9 acetylation at Fasn and Acaca promoters, driving lipogenic gene expression and hepatic steatosis.\",\n      \"method\": \"Liver-specific ACSS2 knockdown mice, CUT&RUN (H3K9ac at Fasn/Acaca promoters), Co-IP (PCAF-H3K9), nuclear fractionation, ethanol feeding model\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CUT&RUN, Co-IP, liver-specific KD with defined chromatin phenotype; single lab\",\n      \"pmids\": [\"37183518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 binds CBP to mediate histone acetylation and regulate hepcidin (HAMP1/2) transcription; ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and hepatocyte ferroptosis in alcoholic liver disease.\",\n      \"method\": \"ACSS2 KO/overexpression, Co-IP (ACSS2-CBP), histone acetylation at HAMP1/2 promoters, iron metabolism measurements, ferroptosis assays, HAMP1/2 rescue overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, chromatin acetylation at defined promoters, rescue experiments; single lab\",\n      \"pmids\": [\"40593779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRF2 transcriptionally upregulates ACSS2 in esophageal squamous cell carcinoma cells; ACSS2 converts ethanol-derived acetate to acetyl-CoA, increasing ATP levels and driving lipid synthesis and invasive capability in NRF2-high cells exposed to ethanol.\",\n      \"method\": \"NRF2/ACSS2 siRNA knockdown, acetyl-CoA/ATP metabolic measurements, lipid synthesis assays, invasion assays, ethanol exposure\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with metabolic and functional readouts; single lab\",\n      \"pmids\": [\"32776152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SREBP-1 directly regulates ACSS2 transcription by binding an SRE element at −475 to −483 bp on the ACSS2 promoter as demonstrated by luciferase reporter and ChIP assay; simultaneous knockdown of ACSS2 and ACLY reduces de novo fatty acid synthesis, TAG synthesis, and lipid droplet formation in mammary epithelial cells.\",\n      \"method\": \"Luciferase reporter assay, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, TAG content measurement, lipid droplet staining\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay and ChIP for promoter regulation, KD with metabolic phenotype; single lab\",\n      \"pmids\": [\"28407230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Alternative transcription start site selection in ACSS2 generates two isoforms (ACSS2-S1 and ACSS2-S2) with different subcellular localizations: ACSS2-S1 is cytoplasmic, while ACSS2-S2 distributes in both nucleus and cytoplasm. ACSS2-S2 overexpression promotes cell proliferation, invasion, and ribosome biogenesis in hepatocellular carcinoma, whereas ACSS2-S1 does not.\",\n      \"method\": \"Transcription start site sequencing, subcellular fractionation/immunofluorescence, isoform-specific overexpression, proliferation/invasion assays, ribosome biogenesis analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, isoform localization with functional readout but limited mechanistic depth\",\n      \"pmids\": [\"31076106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 interacts with HMGCS1 (by Co-IP) to regulate lipid metabolism reprogramming and the PI3K/AKT/mTOR pathway in pancreatic neuroendocrine neoplasms; HMGCS1 overexpression reverses the lipogenic and pro-tumorigenic effects of ACSS2 knockdown.\",\n      \"method\": \"Co-IP (ACSS2-HMGCS1), CCK-8/colony formation/EdU proliferation assays, transwell invasion, nude mouse xenografts, PI3K/AKT/mTOR pathway analysis\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional rescue; single lab, limited mechanistic detail\",\n      \"pmids\": [\"38263056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SCAP N-glycosylation increases both SREBP-1-mediated ACSS2 transcription and AMPK-mediated S659 phosphorylation of ACSS2, promoting nuclear ACSS2 accumulation and H3K27 acetylation, which drives lipogenic gene expression and hepatic inflammation in NASH.\",\n      \"method\": \"SCAP N-glycosylation site mutagenesis, ACSS2 expression/localization assays, AMPK phosphorylation assay, H3K27ac measurements, lipid accumulation assays in hepatic cell lines\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis, defined phosphorylation event, chromatin acetylation, and functional phenotype; single lab\",\n      \"pmids\": [\"38591127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 promotes neuronal TPH2 transcription by binding PPARγ as a co-activator and supporting histone acetylation at the TPH2 promoter; ACSS2 is required for SCFA-mediated antidepressant responses, and PPARγ is identified as a novel ACSS2 partner for activating CRTC1 transcription.\",\n      \"method\": \"Stereotaxic AAV-mediated neuronal ACSS2 knockdown, Co-IP/interaction assay (ACSS2-PPARγ), ChIP (histone acetylation at TPH2/CRTC1 promoters), behavioral tests (chronic-restraint-stress model)\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, in vivo KD with behavioral phenotype; single lab\",\n      \"pmids\": [\"38939042\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSS2 is a nucleocytosolic enzyme that converts acetate (and, under specific signaling contexts, lactate) to acetyl-CoA or lactyl-CoA; it is regulated by AMPK-mediated S659 phosphorylation (promoting nuclear translocation under nutrient stress), ERK-mediated S267 phosphorylation (promoting nuclear translocation downstream of EGFR), and CDK5-mediated S267 phosphorylation (stabilizing ACSS2 protein via reduced ubiquitination); in the nucleus, ACSS2 associates with TFEB, KAT2A, CBP, PCAF, and PPARγ to locally regenerate acetyl-CoA from histone deacetylation-derived acetate for targeted histone acetylation at gene promoters governing lysosomal biogenesis, autophagy, lipogenesis, immune evasion, and stress responses, while its cytosolic pool supports de novo lipogenesis, fatty acid synthesis, and metabolic acetyl-CoA supply for diverse cellular processes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate to acetyl-CoA (and lactate to lactyl-CoA) to fuel both metabolic and epigenetic programs across diverse cell types. In the cytosol, ACSS2-generated acetyl-CoA supports de novo lipogenesis, fatty acid synthesis, and TCA cycle anaplerosis, serving as an essential alternative to ACLY-derived acetyl-CoA when citrate-dependent pathways are compromised [PMID:15, PMID:30228117, PMID:28407230]. Signal-dependent phosphorylation—AMPK at S659 under glucose deprivation or ERK/CDK5 at S267 downstream of EGFR or OGT signaling—drives nuclear translocation, where ACSS2 associates with transcription factors (TFEB, PPARγ, SP1) and acetyltransferases (CBP, KAT2A, PCAF) to locally regenerate acetyl-CoA from deacetylation-released acetate, thereby sustaining targeted histone acetylation, crotonylation, and lactylation at promoters governing autophagy, lysosomal biogenesis, lipogenesis, immune evasion, and stress responses [PMID:28552616, PMID:39561764, PMID:35190642, PMID:38429478, PMID:37183518]. ACSS2 also directly acetylates non-histone substrates—SP1 (K19) to stabilize it and PAICS to promote its autophagic degradation—thereby extending its regulatory reach beyond chromatin to transcription factor stability and purine metabolism [PMID:38429478, PMID:40021646].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that ACSS2 links nutrient stress to transcription factor acetylation: it was unknown how acetyl-CoA was supplied for CBP-mediated HIF-2α acetylation under hypoxia/glucose deprivation; experiments showed ACSS2 is required to convert stress-elevated acetate into acetyl-CoA for CBP/HIF-2α complex formation, connecting metabolic stress sensing to HIF-2 transcriptional activation.\",\n      \"evidence\": \"ACSS2 knockdown/overexpression with HIF-2α acetylation assays, Co-IP, and mouse tumor models\",\n      \"pmids\": [\"25689462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no ChIP to demonstrate chromatin-level mechanism\", \"Direct ACSS2-CBP physical interaction not resolved at this stage\", \"Whether ACSS2 nuclear entry is regulated was not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the AMPK–ACSS2 nuclear translocation axis and chromatin-level recycling mechanism: it was unknown how ACSS2 entered the nucleus or how acetyl-CoA was locally supplied at gene promoters; this work showed AMPK phosphorylates ACSS2 at S659, exposing an NLS for importin-α5 binding, and that nuclear ACSS2 binds TFEB at autophagy/lysosomal gene promoters to recapture histone deacetylation-derived acetate for local acetyl-CoA regeneration and histone H3 acetylation.\",\n      \"evidence\": \"AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2–importin-α5, ACSS2–TFEB), ChIP, nuclear fractionation, knock-in mutants, tumor growth assays\",\n      \"pmids\": [\"28552616\", \"28820290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases also regulate ACSS2 nuclear entry was unresolved\", \"Structural basis of acetate recycling at chromatin not determined\", \"Generality beyond lysosomal/autophagy genes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying transcriptional regulation of ACSS2 by SREBP-1 and its role in de novo lipogenesis: it was unclear how ACSS2 expression itself was controlled; SREBP-1 was shown to directly bind the ACSS2 promoter SRE, and combined ACSS2/ACLY depletion abolished fatty acid and TAG synthesis.\",\n      \"evidence\": \"Luciferase reporter, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, lipid measurements\",\n      \"pmids\": [\"28407230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only tested in mammary epithelial cells\", \"Post-translational regulation of ACSS2 protein levels not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extending ACSS2's chromatin role to non-acetyl acyl modifications and viral latency: it was unknown whether ACSS2 could drive histone crotonylation; ACSS2 was shown to generate crotonyl-CoA that promotes histone crotonylation at the HIV LTR, reactivating latent provirus.\",\n      \"evidence\": \"siRNA knockdown, pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assays, SIV primate model\",\n      \"pmids\": [\"29457784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro crotonyl-CoA synthetase activity of purified ACSS2 was not reconstituted\", \"Whether acetate or crotonate is the physiological substrate for crotonylation was unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating ACSS2's whole-organism role in lipid metabolism: it was unknown whether ACSS2 loss would affect systemic lipid handling; ACSS2 knockout mice showed reduced intestinal lipid absorption and altered triglyceride repartitioning between adipose and liver in a fed/fasted state-dependent manner.\",\n      \"evidence\": \"ACSS2 knockout mice, diet-induced obesity model, gene expression profiling\",\n      \"pmids\": [\"30228117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear versus cytosolic contribution to the metabolic phenotype not dissected\", \"Compensatory changes in ACLY or other acetyl-CoA sources not fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing CDK5-mediated post-translational stabilization of ACSS2: it was unclear how ACSS2 protein levels were regulated; OGT-dependent CDK5 phosphorylation of ACSS2 at S267 was shown to reduce polyubiquitination and degradation, stabilizing ACSS2 and increasing acetyl-CoA and lipid production in glioblastoma.\",\n      \"evidence\": \"Phospho-site mutagenesis (S267), ubiquitination assays, metabolic tracing, in vivo GBM growth\",\n      \"pmids\": [\"35190642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S267 phosphorylation also affects nuclear translocation (as later shown for ERK) was not tested\", \"Identity of the E3 ligase mediating ACSS2 ubiquitination was not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating ACSS2's nuclear role in alcohol-induced hepatic lipogenesis: it was unknown how ethanol-derived acetate reprograms lipogenic chromatin; nuclear ACSS2 was shown to recruit PCAF acetyltransferase for H3K9 acetylation at Fasn and Acaca promoters, driving hepatic steatosis.\",\n      \"evidence\": \"Liver-specific ACSS2 knockdown mice, CUT&RUN, Co-IP (PCAF–H3K9), ethanol feeding model\",\n      \"pmids\": [\"37183518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSS2 directly binds PCAF or acts via intermediate complex not resolved\", \"Contribution relative to ACLY in this context not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending ACSS2's chromatin function to neuronal gene regulation: it was unknown whether ACSS2-dependent histone acetylation controlled synaptic receptor expression; hippocampal ACSS2 overexpression restored H3K9ac and H4K12ac at NMDAR/AMPAR promoters, rescuing synaptic plasticity and cognition in Alzheimer's disease mice.\",\n      \"evidence\": \"AAV-mediated ACSS2 overexpression, ChIP-qPCR, electrophysiology, Morris water maze\",\n      \"pmids\": [\"37438762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based; loss-of-function confirmation in neurodegeneration models lacking\", \"Whether acetate availability is limiting in AD brain not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering ACSS2 as a lactyl-CoA synthetase and defining the EGFR–ERK–ACSS2–KAT2A histone lactylation axis: it was unknown how histone lactylation substrates were generated; ACSS2 was shown to convert lactate to lactyl-CoA downstream of ERK-mediated S267 phosphorylation, and a co-crystal structure revealed lactyl-CoA binding to KAT2A, which then lactylates histone H3 to drive PD-L1 and Wnt/NF-κB expression.\",\n      \"evidence\": \"In vitro lactyl-CoA synthetase assay, co-crystal structure (KAT2A–lactyl-CoA), ERK phosphorylation assay, Co-IP, ChIP, in vivo anti-PD-1 combination\",\n      \"pmids\": [\"39561764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contradicts the 2024 finding that purified ACSS2 cannot use butyrate/crotonate—substrate specificity boundaries for short-chain acids need reconciliation\", \"Whether lactyl-CoA synthesis is kinetically relevant at physiological lactate concentrations in vivo is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Clarifying ACSS2 substrate specificity: it was debated whether ACSS2 could generate crotonyl-CoA or butyryl-CoA; purified recombinant ACSS2 was shown to be unable to use butyrate or crotonate as substrates, restricting its primary activity to acetate-to-acetyl-CoA conversion.\",\n      \"evidence\": \"In vitro enzymatic assay with purified recombinant ACSS2, structural analysis\",\n      \"pmids\": [\"38369012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address the lactyl-CoA synthetase activity reported separately\", \"Cell-based crotonylation attributed to ACSS2 in prior studies remains mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating ACSS2-mediated non-histone substrate acetylation: it was unknown whether ACSS2 directly acetylated non-histone proteins; ACSS2 was shown to acetylate SP1 at K19 (stabilizing SP1 for SAT1-driven polyamine reprogramming) and PAICS (promoting its autophagic degradation to limit purine biosynthesis and dNTP pools, exacerbating senescence-associated phenotypes).\",\n      \"evidence\": \"Co-IP, acetylation mass spectrometry, autophagy flux assays, dNTP measurements, ACSS2 KO mice, SASP profiling; ChIP-seq/RNA-seq for SP1/SAT1 axis in pancreatic cancer models\",\n      \"pmids\": [\"38429478\", \"40021646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACSS2 itself has intrinsic acetyltransferase activity or channels acetyl-CoA to an acetyltransferase for these substrates is not fully distinguished\", \"Range of non-histone substrates likely incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing ACSS2 as a compensatory acetyl-CoA source maintaining T cell effector chromatin: it was unknown whether ACSS2 could sustain epigenetic and metabolic programs when the primary ACLY pathway was absent; double-KO epistasis with 13C-acetate tracing showed ACSS2 maintains TCA fueling, histone acetylation, and chromatin accessibility at effector gene loci in CD8 T cells.\",\n      \"evidence\": \"ACLY KO, ACSS2 KO, double KO, 13C-acetate tracing, ATAC-seq, in vivo infection models\",\n      \"pmids\": [\"39150482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ACSS2 versus ACLY under normal (non-KO) physiological conditions not quantified\", \"Whether this compensation operates in other immune cell types untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking ACSS2-driven lipogenesis to NLRP3 pyroptosis and kidney fibrosis: it was unknown how acetate metabolism caused tubular injury; ACSS2-produced acetyl-CoA was shown to drive de novo lipogenesis that depletes NADPH and elevates ROS, activating NLRP3-dependent pyroptosis; separately, ACSS2-produced crotonyl-CoA drives H3K9 crotonylation at the IL-1β locus, amplifying inflammation.\",\n      \"evidence\": \"ACSS2 KO mice, primary tubular cells, NADPH/ROS measurements, NLRP3 pathway, ChIP-seq/RNA-seq for H3K9cr, multiple fibrosis models\",\n      \"pmids\": [\"38051585\", \"38615014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ACSS2 generates crotonyl-CoA given its inability to use crotonate in vitro is mechanistically unexplained\", \"Relative importance of lipogenesis-ROS versus H3K9cr-IL-1β arms not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining ACSS2 as a PPARγ co-activator coupling activation to degradation in adipose plasticity: it was unknown how PPARγ activity was homeostatically regulated; ACSS2 was shown to bind acetylated PPARγ, recruit SIRT1 and PRDM16 for UCP1 activation, then facilitate PPARγ polyubiquitination and degradation via P300.\",\n      \"evidence\": \"Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), ubiquitination assays, ACSS2 KO mice, high-fat diet model\",\n      \"pmids\": [\"38332049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequential model (activation then degradation) not validated by real-time dynamics\", \"Structural basis of ACSS2–PPARγ interaction not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connecting ACSS2–CBP to iron homeostasis regulation: it was unknown how acetyl-CoA metabolism influenced hepcidin transcription; ACSS2 was shown to bind CBP and maintain histone acetylation at HAMP1/2 promoters, with ACSS2 deficiency causing hepcidin downregulation, systemic iron dyshomeostasis, and hepatocyte ferroptosis in alcoholic liver disease.\",\n      \"evidence\": \"ACSS2 KO/overexpression, Co-IP (ACSS2–CBP), histone acetylation at HAMP promoters, iron metabolism and ferroptosis assays, rescue experiments\",\n      \"pmids\": [\"40593779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the iron phenotype is direct or secondary to broader chromatin accessibility changes not resolved\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) how ACSS2 generates crotonyl-CoA and lactyl-CoA in cells given its in vitro restriction to acetate; (2) whether ACSS2 possesses intrinsic protein acetyltransferase activity or solely channels acetyl-CoA to partner acetyltransferases; (3) the structural basis of ACSS2's association with diverse transcription factor and acetyltransferase partners; and (4) the relative quantitative contributions of ACSS2 versus ACLY to chromatin acetylation under physiological (non-KO) conditions in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length ACSS2 in complex with nuclear partners\", \"No kinetic comparison of ACSS2 lactyl-CoA vs acetyl-CoA synthetase activity under physiological substrate concentrations\", \"Tissue-specific isoform functions (ACSS2-S1 vs ACSS2-S2) remain poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 7, 14, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 12, 25]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4, 10, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3, 8, 16, 18, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 9, 15, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 4, 8, 10, 16, 18, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 7, 9, 15, 20, 21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 18, 19, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TFEB\", \"KAT2A\", \"CBP\", \"PCAF\", \"PPARγ\", \"SP1\", \"PAICS\", \"SIRT1\"],\n    \"other_free_text\": []\n  }\n}\n```"}