{"gene":"ACSS2","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":2017,"finding":"Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, exposing a nuclear localization signal that binds importin α5 (KPNA1), enabling nuclear translocation. In the nucleus, ACSS2 forms a complex with transcription factor EB (TFEB) at lysosomal and autophagy gene promoters, where it locally converts acetate (derived from histone deacetylation turnover) to acetyl-CoA to support histone H3 acetylation at these loci, promoting lysosomal biogenesis and autophagy.","method":"AMPK kinase assay, phospho-site mutagenesis (S659A knock-in), co-immunoprecipitation (ACSS2–importin α5, ACSS2–TFEB), ChIP-seq at lysosomal/autophagy gene promoters, nuclear fractionation, glioblastoma cell and mouse brain tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phospho-site mutagenesis, reconstituted nuclear translocation mechanism, ChIP-seq, reciprocal Co-IP, functional rescue with multiple mutant knock-ins in cells and in vivo; replicated in companion Autophagy paper (PMID:28820290)","pmids":["28552616","28820290"],"is_preprint":false},{"year":2024,"finding":"EGFR activation drives ERK-mediated phosphorylation of ACSS2 at S267, promoting its nuclear translocation and complex formation with lysine acetyltransferase KAT2A. ACSS2 functions as a bona fide lactyl-CoA synthetase, converting lactate to lactyl-CoA; co-crystal structure shows lactyl-CoA bound to KAT2A, which then acts as a lactyltransferase to lactylate histone H3, driving Wnt/β-catenin, NF-κB, and PD-L1 expression.","method":"In vitro lactyl-CoA synthetase assay with purified ACSS2, co-crystal structure of lactyl-CoA–KAT2A complex, ERK phosphorylation assay, Co-IP (ACSS2–KAT2A), ChIP, S267 mutagenesis, interaction-blocking peptide experiments, mouse brain tumor models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic reconstitution in vitro, co-crystal structure with functional validation, phospho-site mutagenesis, reciprocal Co-IP, multiple orthogonal methods in one rigorous study","pmids":["39561764"],"is_preprint":false},{"year":2025,"finding":"ACSS2 functions as a β-hydroxybutyryl-CoA (BHB-CoA) synthetase by converting β-hydroxybutyrate to BHB-CoA in the nucleus, where it co-localizes with lysine acetyltransferase KAT7. KAT7 acts as a β-hydroxybutyryltransferase that preferentially catalyzes histone H3K9 β-hydroxybutyrylation (H3K9bhb) using ACSS2-generated BHB-CoA, linking ketone metabolism to epigenetic transcriptional activation.","method":"In vitro BHB-CoA synthetase assay with purified ACSS2, mass spectrometry identification of 1171 Kbhb substrates, Co-IP (ACSS2–KAT7), chromatin co-localization, ChIP, KAT7 acetyltransferase assays, nuclear fractionation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic reconstitution, Co-IP, ChIP, mass spectrometry; single lab but multiple orthogonal methods","pmids":["40815653"],"is_preprint":false},{"year":2024,"finding":"ACSS2 directly interacts with and promotes acetylation of PAICS (a key purine biosynthesis enzyme) at the K site; this acetylation triggers autophagy-mediated PAICS degradation, limiting purine metabolism and dNTP pools, which exacerbates cytoplasmic chromatin fragment accumulation and the senescence-associated secretory phenotype (SASP).","method":"Co-IP (ACSS2–PAICS), acetylation site mutagenesis, autophagy flux assays, dNTP pool measurement, Acss2 KO mouse model, pharmacological ACSS2 inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, genetic KO in mice with multiple orthogonal readouts; single lab","pmids":["40021646"],"is_preprint":false},{"year":2018,"finding":"ACSS2 produces crotonyl-CoA (from crotonate), and its increased expression reprograms chromatin at the HIV LTR through histone crotonylation, raising histone acetylation and reducing histone methylation to reactivate latent HIV. siRNA knockdown or pharmacological inhibition of ACSS2 diminishes histone crotonylation-induced HIV reactivation.","method":"siRNA knockdown, pharmacological inhibition, ChIP at HIV LTR (histone crotonylation/acetylation/methylation marks), latent HIV reactivation assay, SIV-infected non-human primate model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, siRNA/pharmacological inhibition, in vivo NHP model; single lab; note: subsequent in vitro study (PMID:38369012) shows ACSS2 does NOT generate crotonyl-CoA from crotonate, creating a direct conflict — confidence lowered accordingly","pmids":["29457784"],"is_preprint":false},{"year":2024,"finding":"In vitro experiments with purified/recombinant ACSS2 demonstrate that ACSS2 is UNABLE to generate butyryl-CoA or crotonyl-CoA from butyrate or crotonate; ACSS2 activity is restricted to acetyl-CoA synthesis from acetate.","method":"Direct in vitro enzymatic assay with purified and recombinant ACSS2, structural analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified enzyme plus structural considerations; single lab but definitive biochemical result contradicting prior claims","pmids":["38369012"],"is_preprint":false},{"year":2015,"finding":"ACSS2 is required for acetylation of HIF-2α by the acetyltransferase CBP (CREB-binding protein) during hypoxia and glucose deprivation; acetate levels increase during stress and coincide with maximal HIF-2α acetylation and stable CBP/HIF-2α complex formation. ACSS2 translocates from cytosol to nucleus under stress.","method":"Co-immunoprecipitation (CBP–HIF-2α), acetylation assays, nuclear fractionation, ACSS2/HIF-2 siRNA knockdown, colony formation/migration/invasion assays, flank tumor mouse model with exogenous acetate","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, nuclear fractionation, siRNA depletion, in vivo mouse model; single lab, replicated in follow-up papers (PMID:29281714, PMID:36862715)","pmids":["25689462","29281714"],"is_preprint":false},{"year":2022,"finding":"O-GlcNAc transferase (OGT) regulates ACSS2 stability by promoting CDK5-dependent phosphorylation of ACSS2 at Ser-267, which reduces ACSS2 polyubiquitination and proteasomal degradation, thereby increasing acetate-to-acetyl-CoA conversion and lipid production in glioblastoma cells.","method":"CDK5 kinase assay, S267 phospho-mimetic/phospho-null mutagenesis, ubiquitination assay, OGT overexpression/inhibition, Co-IP, in vitro and in vivo GBM growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phospho-site mutagenesis, ubiquitination assay, kinase assay, in vivo rescue; single lab but multiple orthogonal methods","pmids":["35190642"],"is_preprint":false},{"year":2025,"finding":"Under amino acid deficiency, SIRT2 deacetylates ACSS2 at lysine K271, which promotes K271 ubiquitination and subsequent proteasomal degradation of ACSS2, suppressing de novo lipogenesis. Substitution of K271 decreases ubiquitination, stabilizes ACSS2, and increases lipogenesis.","method":"SIRT2 deacetylation assay in vitro, K271 mutagenesis, ubiquitination assay, lipogenesis measurement, nutrient-stress cell culture experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro deacetylation assay, site-directed mutagenesis, ubiquitination assay; single lab with multiple orthogonal methods","pmids":["40331334"],"is_preprint":false},{"year":2018,"finding":"Mice lacking ACSS2 show reduced body weight and hepatic steatosis under diet-induced obesity, with reduced intestinal lipid absorption and impaired repartitioning of triglycerides from adipose tissue to liver due to lowered expression of lipid transporters and fatty acid oxidation genes, demonstrating that ACSS2 promotes systemic fat storage and utilization through selective regulation of lipid metabolism genes.","method":"ACSS2 knockout mice, diet-induced obesity model, gene expression profiling, body composition analysis, lipid absorption assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with clear phenotypic readout in multiple metabolic parameters; single lab but in vivo with rigorous controls","pmids":["30228117"],"is_preprint":false},{"year":2017,"finding":"ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus (HCMV)-induced lipogenesis and viral growth; ACSS2-KO human fibroblasts (via CRISPR/Cas9) exhibit sharply reduced HCMV-induced lipogenesis and viral replication. Glucose-derived acetate (produced non-enzymatically from pyruvate) is the substrate used by ACSS2 in HCMV-infected cells.","method":"CRISPR/Cas9 ACSS2 knockout human fibroblasts, 13C isotope tracing, viral growth assays, lipogenesis measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CRISPR KO with isotope tracing and functional viral growth readout; single lab, multiple orthogonal methods","pmids":["28167750"],"is_preprint":false},{"year":2021,"finding":"A transition-state mimetic small-molecule inhibitor of ACSS2 blocks ACSS2 enzymatic activity in vitro and in vivo, impairing breast tumor growth as a single agent, validating ACSS2 as a druggable acetate-to-acetyl-CoA enzyme in cancer.","method":"In vitro ACSS2 enzyme inhibition assay, cell viability assays, mouse xenograft tumor model with pharmacologic ACSS2 inhibitor","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with inhibitor, in vivo tumor model; single lab but transition-state mimetic provides mechanistic evidence of enzymatic targeting","pmids":["33414169"],"is_preprint":false},{"year":2017,"finding":"SREBP-1 directly regulates ACSS2 gene transcription by binding to a sterol response element (SRE) at −475 to −483 bp on the ACSS2 promoter, as shown by luciferase reporter assay and SREBP-1 interaction with the SRE site.","method":"Luciferase reporter assay, siRNA knockdown of ACSS2 and ACLY, RT-qPCR, lipid droplet quantification","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase reporter with SRE mutagenesis and siRNA knockdown; single lab","pmids":["28407230"],"is_preprint":false},{"year":2024,"finding":"ACSS2 channels stroma-derived acetate into epigenetic regulation in pancreatic cancer cells, mediating acetylation of the transcription factor SP1 at lysine 19 residue, increasing SP1 protein stability and transcriptional activity. This promotes SAT1 gene expression via the ACSS2-SP1-SAT1 axis, altering polyamine homeostasis and enabling cancer cell survival under acidosis.","method":"H3K27ac ChIP-seq, RNA-seq, Co-IP (ACSS2–SP1), mass spectrometry (SP1 K19 acetylation), siRNA/pharmacological inhibition, mouse tumor models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq, mass spectrometry acetylation site identification, Co-IP, in vivo tumor models; single lab but multiple orthogonal methods","pmids":["38429478"],"is_preprint":false},{"year":2024,"finding":"ACSS2 regulates de novo lipogenesis (DNL) in kidney tubular cells, causing NADPH depletion and increased ROS levels, ultimately leading to NLRP3-dependent pyroptosis. ACSS2-KO mice are protected from kidney fibrosis in multiple disease models.","method":"ACSS2 KO mice, primary tubular cell cultures, NADPH/ROS measurement, NLRP3 inhibition, pharmacological inhibition of fatty acid synthase, DNL flux assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO, multiple disease models, mechanistic pathway dissection with pharmacological controls; single lab but multiple orthogonal methods","pmids":["38051585"],"is_preprint":false},{"year":2019,"finding":"Alternative transcription start site selection of ACSS2 produces two isoforms (ACSS2-S1 and ACSS2-S2) with different subcellular localizations: ACSS2-S1 localizes predominantly to the cytoplasm while ACSS2-S2 distributes to both nucleus and cytoplasm. Only ACSS2-S2 overexpression promotes HCC cell proliferation and invasion, correlating with enhanced ribosome biogenesis.","method":"Alternative TSS analysis, subcellular fractionation, overexpression of individual isoforms, cell proliferation and invasion assays, ribosome biogenesis analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fractionation plus functional overexpression assays with two isoforms; single lab","pmids":["31076106"],"is_preprint":false},{"year":2024,"finding":"ACSS2 inhibition in clear cell RCC reduces HIF-2α protein levels and stability through a pVHL-independent pathway involving the E3 ligase MUL1, which directly interacts with HIF-2α; ACSS2 inhibition decreases chromatin accessibility at the HIF-2α locus, reducing HIF-2α expression and suppressing ccRCC growth.","method":"ACSS2 pharmacological inhibition, MUL1 Co-IP with HIF-2α, MUL1 overexpression (HIF-2α level reduction), ATAC-seq (chromatin accessibility), primary patient tumor cultures, in vivo ccRCC models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP (MUL1–HIF-2α), ATAC-seq, primary patient tumor models; single lab, pathway not fully reconstituted","pmids":["38941296"],"is_preprint":false},{"year":2024,"finding":"ACSS2 controls PPARγ activity homeostasis by binding directly to acetylated PPARγ in the presence of ligand, recruiting SIRT1 and PRDM16 to activate UCP1 expression. SIRT1 then deacetylates PPARγ and triggers ACSS2 translocation from PPARγ to P300, inducing PPARγ polyubiquitination and degradation, thereby coupling PPARγ activation with its degradation to enhance adipose tissue plasticity.","method":"Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), PPARγ acetylation/ubiquitination assays, ACSS2 KO and overexpression in mice, UCP1/thermogenesis readouts","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, in vivo mouse model; single lab","pmids":["38332049"],"is_preprint":false},{"year":2023,"finding":"In CD8 T cells, ACSS2 provides an alternative acetate-dependent pathway for cytosolic acetyl-CoA production when ACLY is ablated. ACSS2-derived acetyl-CoA supports histone acetylation and chromatin accessibility at effector gene loci, maintaining CD8 T cell effector function. When ACLY is functional, ACSS2 is not required for this process.","method":"Conditional ACLY and/or ACSS2 KO in CD8 T cells, infection models, ATAC-seq, 13C acetate tracing, histone acetylation ChIP","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional double KO, isotope tracing, ATAC-seq, infection model with functional readouts; single lab but multiple orthogonal methods","pmids":["39150482"],"is_preprint":false},{"year":2023,"finding":"ACSS2 promotes alkaliptosis in pancreatic cancer cells by producing acetyl-CoA that supports histone acetylation contributing to NF-κB-dependent downregulation of carbonic anhydrase 9 (CA9). ACSS2 knockdown blocks JTC801-induced alkaliptosis and NF-κB-mediated CA9 downregulation.","method":"shRNA knockdown, qPCR, western blot, cell death assays, histone deacetylase inhibitor (TSA) combination, ACSS2 knockdown + NF-κB reporter","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA/shRNA with mechanistic follow-up; single lab, limited reconstitution","pmids":["36707625"],"is_preprint":false},{"year":2024,"finding":"Alcohol downregulates hepatic ACSS2, leading to acetate accumulation. ACSS2 binds CREB-binding protein (CBP) to mediate histone acetylation and regulate hepcidin (HAMP1/2) transcription; ACSS2 deficiency downregulates HAMP1/2, causing iron dyshomeostasis and ferroptosis in alcoholic liver disease. Overexpression of HAMP1/2 rescues the ferroptosis phenotype caused by ACSS2 deficiency.","method":"Co-IP (ACSS2–CBP), ChIP (H3K27ac at HAMP1/2 promoters), ACSS2 KO mice, HAMP1/2 rescue overexpression, iron chelator/ferroptosis inhibitor treatment, alcohol-fed mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, genetic KO with rescue experiment, in vivo mouse model; single lab but multiple orthogonal methods","pmids":["40593779"],"is_preprint":false},{"year":2023,"finding":"Alcohol metabolism promotes nuclear translocation of ACSS2 in hepatocytes; nuclear ACSS2 supports acetyl-CoA production for H3K9 acetylation at lipogenic gene (Fasn, Acaca) promoters via PCAF (but not GCN5, CBP, or p300), driving de novo lipogenesis and hepatic steatosis. Liver-specific ACSS2 knockdown blocks PCAF–H3K9 interaction and suppresses lipogenic gene induction.","method":"Nuclear fractionation, CUT&RUN (H3K9ac at promoters), Co-IP (PCAF–H3K9ac), liver-specific ACSS2 knockdown mice, ethanol/acetate treatment of hepatocytes","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — CUT&RUN, Co-IP, liver-specific KD in vivo; single lab","pmids":["37183518"],"is_preprint":false},{"year":2024,"finding":"ACSS2 inhibition triggers its nuclear translocation (under glycolytic inhibition context), increasing SIRT1 expression; nuclear SIRT1 then deacetylates ATG5 and ATG2B, activating autophagy in ovarian cancer cells. ACSS2 inhibition also suppresses HXK2-dependent glycolysis.","method":"CUT&TAG, Co-IP, ACSS2 knockdown, SIRT1 inhibitor experiments, autophagy flux assays, ATG5/ATG2B acetylation analysis, Seahorse metabolic assay","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — CUT&TAG, Co-IP, multiple functional assays; single lab","pmids":["39362518"],"is_preprint":false},{"year":2024,"finding":"ACSS2 interacts with HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) in pancreatic neuroendocrine neoplasms as shown by Co-IP; ACSS2 regulates lipid metabolism reprogramming and activates the PI3K/AKT/mTOR pathway. HMGCS1 overexpression reverses the effects of ACSS2 knockdown on lipid metabolism and PI3K/AKT/mTOR pathway.","method":"Co-IP (ACSS2–HMGCS1), siRNA knockdown, HMGCS1 overexpression rescue, lipid metabolism assays, PI3K/AKT/mTOR pathway analysis, xenograft mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional rescue experiments; single lab","pmids":["38263056"],"is_preprint":false},{"year":2024,"finding":"ACSS2 binds directly to PPARγ and TFEB as obligatory mediators for their co-activation of TPH2 transcription in neurons; short-chain fatty acids (SCFAs) activate ACSS2, which promotes TPH2 promoter histone acetylation and transcription. ACSS2 nuclear translocation is required for SCFA-mediated antidepressant responses and depends on AMPK activation.","method":"Stereotaxic AAV-mediated ACSS2 knockdown in hippocampus, Co-IP (ACSS2–PPARγ, ACSS2–TFEB), ChIP (H3ac at TPH2 promoter), behavioral assays, AMPK inhibitor experiments","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ChIP, in vivo AAV knockdown with behavioral readout; single lab","pmids":["38939042"],"is_preprint":false},{"year":2025,"finding":"ACSS2 mediates H4K12 acetylation and H3K27 acetylation in hepatic stellate cells (HSCs) under SREBP2 transcriptional control; SREBP2 directly binds the ACSS2 promoter to activate ACSS2 transcription. HSC-specific ACSS2 deletion ameliorates liver fibrosis, and ACSS2 inhibition suppresses TGFβ1-induced primary human HSC activation.","method":"CUT&Tag-seq (SREBP2 at ACSS2 promoter), RNA-seq, HSC-specific ACSS2 KO mice, ACSS2 ectopic overexpression rescue, pharmacological ACSS2 inhibition, human liver biopsy validation","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag-seq, genetic KO, human validation; single lab","pmids":["41887397"],"is_preprint":false},{"year":2026,"finding":"ACSS2 mediates crotonate-to-crotonyl-CoA conversion (in this study's context via p300 as acyltransferase), and ACSS2-generated crotonyl-CoA fuels p300-catalyzed crotonylation of EZH2 at K348, leading to EZH2 ubiquitination and degradation, reducing genome-wide H3K27me3.","method":"In vitro crotonylation assay, mass spectrometry (EZH2-K348cr), Co-IP (ACSS2–p300–EZH2), H3K27me3 ChIP-seq, EZH2 ubiquitination assay, mouse breast cancer models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro assay, mass spectrometry, Co-IP, ChIP-seq; single lab; note: conflicts with PMID:38369012 showing ACSS2 cannot generate crotonyl-CoA — confidence limited","pmids":["41544165"],"is_preprint":false},{"year":2026,"finding":"In oligodendrocyte progenitor cells (OPCs), ACSS2-mediated histone H4K12 and H3K27 acetylation enhances expression of Gria2 (an AMPA receptor subunit critical for OPC proliferation). Deletion of ACSS2 in the oligodendrocyte lineage reduces OPC population, impairs myelinogenesis, and exacerbates age-related cognitive deficits; acetate supplementation (ACSS2 substrate) preserves OPCs and promotes remyelination.","method":"OPC-specific ACSS2 KO mice, ChIP (H4K12ac, H3K27ac at Gria2 locus), acetate supplementation rescue, myelination assays, cognitive function tests","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Moderate — lineage-specific KO, ChIP, acetate supplementation rescue, in vivo myelin and cognitive readouts; single lab but multiple orthogonal methods","pmids":["41781676"],"is_preprint":false},{"year":2024,"finding":"ACSS2 inhibition in breast cancer brain metastatic cells suppresses ferroptosis via an E2F1-mediated transcriptional mechanism regulating anti-ferroptotic proteins SLC7A11 and GPX4; ACSS2-S267D phospho-mimetic is required for in vivo brain (but not mammary fat pad) tumor growth, implicating OGT/CDK5-mediated S267 phosphorylation as critical for brain-specific ACSS2 function.","method":"ACSS2 S267D phospho-mimetic expression, E2F1 ChIP at SLC7A11/GPX4 promoters, ferroptosis assays, in vivo brain vs mammary fat pad tumor growth comparison, pharmacological ACSS2 inhibitor ex vivo/in vivo","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — phospho-mimetic, ChIP, in vivo comparison; preprint, single lab","pmids":["39484430"],"is_preprint":true},{"year":2025,"finding":"ACSS2 mediates β-cell adaptation to pregnancy stress by supporting acetyl-CoA biosynthesis; STAT3 recruits p300 to promote histone acetylation of pregnancy-associated genes, a process enhanced by ACSS2. β-cell-specific deletion of Acss2 rescues HFD-induced impairment of β-cell function during gestation.","method":"Single-cell transcriptomics, β-cell-specific ACSS2 KO mice, ChIP (H3ac at pregnancy-associated gene promoters), STAT3/p300 Co-IP, gestational diabetes model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO, ChIP, Co-IP, single-cell transcriptomics; single lab","pmids":["40393969"],"is_preprint":false},{"year":2024,"finding":"ACSS2-mediated H3K9 crotonylation increases IL-1β expression in kidney tubular epithelial cells during fibrosis; genetic and pharmacological inhibition of ACSS2 suppresses H3K9cr-mediated IL-1β expression, alleviating IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis.","method":"ChIP-seq (H3K9cr), RNA-seq, ACSS2 KO mice, pharmacological ACSS2 inhibition, macrophage activation assay, tubular cell senescence assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, RNA-seq, genetic KO, pharmacological inhibition with specific cellular readouts; single lab; note: conflicts with PMID:38369012 (ACSS2 cannot make crotonyl-CoA) — lower confidence for the crotonylation mechanism specifically","pmids":["38615014"],"is_preprint":false},{"year":2020,"finding":"Acetate promotes SNAI1 expression via ACSS2-mediated histone H3K27 acetylation at the SNAI1 regulatory region under glucose limitation; ACSS2 knockdown decreases acetate-induced SNAI1 expression and cell migration, while ACSS2 overexpression increases H3K27ac and SNAI1 levels. ChIP showed increased H3K27ac at the SNAI1 locus but no increase in ACSS2 direct binding.","method":"ChIP (H3K27ac at SNAI1 locus), siRNA knockdown of ACSS2, ACSS2 overexpression, wound healing and invasion assays","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP, siRNA, overexpression; single lab","pmids":["32458971"],"is_preprint":false},{"year":2023,"finding":"Loss of ACSS2 in mice leads to tissue-specific dysregulation of canonical signaling pathways and transcription factor networks in liver, brain, and mesenteric adipose tissue, demonstrating that ACSS2 acts as a transcriptional regulatory enzyme; however, ACSS2 loss resulted in few changes in fatty acid constitution across these tissues.","method":"Acss2 KO mice, transcriptomic analysis (RNA-seq) of liver, brain, and adipose, fatty acid composition analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO transcriptomics with fatty acid measurement; single lab, descriptive mechanistic interpretation","pmids":["36835088"],"is_preprint":false},{"year":2024,"finding":"Acss2 KO mice consume significantly less voluntary alcohol and exhibit blunted gene expression in the ventral striatum following drinking, associated with depletion of ventral striatal H3K27ac. This demonstrates ACSS2 is required for alcohol-derived acetate incorporation into histone acetylation marks in brain reward circuits.","method":"Acss2 KO mice, binge drinking model, genome-wide transcriptional profiling (7 brain regions), H3K27ac ChIP in ventral striatum","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, ChIP, genome-wide transcriptomics; single lab","pmids":["39653249"],"is_preprint":false},{"year":2025,"finding":"ACSS2 promotes temozolomide resistance in pancreatic neuroendocrine tumors by mediating acetate-to-acetyl-CoA conversion, causing histone hyperacetylation that promotes BCL6 transcription. BCL6 then binds the TP53 promoter and silences p53 expression, bypassing DNA damage-induced apoptosis.","method":"Single-cell RNA-seq, ChIP (BCL6 at TP53 promoter, H3ac at BCL6 locus), ACSS2 KI/KO, patient-derived organoids, immunocompetent Rip1-Tag2 mice, ACSS2 inhibitor + anti-PD1 combination","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, organoids, in vivo mouse model; single lab","pmids":["41786280"],"is_preprint":false}],"current_model":"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate (and β-hydroxybutyrate) to their cognate acyl-CoAs; it is regulated by AMPK-mediated S659 phosphorylation and CDK5-mediated S267 phosphorylation (stabilizing it from ubiquitination), and counter-regulated by SIRT2-mediated K271 deacetylation (promoting its degradation), while in the nucleus it binds transcription factors (TFEB, HIF-2α/CBP, KAT2A, KAT7, PPARγ, SP1, AATF) and locally regenerates acetyl-CoA or BHB-CoA from deacetylation-derived metabolites to support histone H3 acetylation, β-hydroxybutyrylation, and lactylation at specific gene promoters governing autophagy, lysosomal biogenesis, lipid metabolism, immune evasion, and stress responses."},"narrative":{"mechanistic_narrative":"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate to acetyl-CoA and serves as a metabolic-epigenetic hub coupling nutrient and stress states to histone acylation and gene transcription [PMID:38369012, PMID:39561764]. Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, exposing a nuclear localization signal that engages importin α5 to drive nuclear translocation, where ACSS2 complexes with TFEB at lysosomal and autophagy gene promoters and locally regenerates acetyl-CoA from deacetylation-derived acetate to support promoter H3 acetylation [PMID:39561764]. Its stability and localization are controlled by post-translational modification: OGT-driven CDK5 phosphorylation at S267 (and EGFR/ERK signaling at the same residue) protects ACSS2 from polyubiquitination while promoting nuclear translocation [PMID:35190642, PMID:39561764], whereas SIRT2 deacetylation of K271 promotes K271 ubiquitination and proteasomal degradation, suppressing lipogenesis [PMID:40331334]. In the nucleus ACSS2 acts as a substrate-providing partner for diverse acyltransferases: it functions as a lactyl-CoA synthetase supplying lactyl-CoA to KAT2A for histone lactylation [PMID:39561764], and as a β-hydroxybutyryl-CoA synthetase supplying BHB-CoA to KAT7 for H3K9 β-hydroxybutyrylation [PMID:40815653]. Through these activities ACSS2 also directly binds transcription factors and chromatin regulators—HIF-2α/CBP [PMID:25689462, PMID:29281714], SP1 [PMID:38429478], PPARγ [PMID:38332049], and PCAF/p300-linked complexes [PMID:37183518]—to acetylate substrates and activate target loci governing immune evasion, polyamine homeostasis, adipose plasticity, and lipogenesis. At the systemic level, ACSS2 promotes de novo lipogenesis and fat storage, and its genetic loss alters lipid metabolism gene programs and protects against diet-induced steatosis, kidney fibrosis, and liver fibrosis [PMID:30228117, PMID:38051585, PMID:41887397]. ACSS2 is enzymatically restricted to acetate in rigorous in vitro reconstitution, which conflicts with cellular reports of crotonyl-CoA, butyryl-CoA, and related acyl-CoA generation [PMID:38369012, PMID:29457784, PMID:41544165]. A transition-state mimetic inhibitor validates ACSS2 as a druggable target in cancer [PMID:33414169].","teleology":[{"year":2015,"claim":"Established that ACSS2 acts beyond cytosolic metabolism by translocating to the nucleus under stress to enable transcription-factor acetylation, answering whether acetate metabolism feeds nuclear signaling.","evidence":"Co-IP of CBP–HIF-2α, nuclear fractionation, and siRNA depletion with in vivo tumor model under hypoxia/glucose deprivation","pmids":["25689462","29281714"],"confidence":"Medium","gaps":["Did not define the kinase or signal triggering nuclear translocation","Direct ACSS2 enzymatic activity at the locus not reconstituted"]},{"year":2017,"claim":"Resolved the molecular mechanism of stress-induced nuclear targeting, showing AMPK-S659 phosphorylation unmasks an NLS for importin α5 and that nuclear ACSS2 locally regenerates acetyl-CoA at TFEB target promoters to drive autophagy/lysosomal genes.","evidence":"AMPK kinase assay, S659A knock-in, ACSS2–importin α5 and ACSS2–TFEB Co-IP, ChIP-seq in glioblastoma cells and mouse brain tumors","pmids":["28552616","28820290"],"confidence":"High","gaps":["Quantitative contribution of local vs bulk acetyl-CoA pools unresolved","Generality of the TFEB axis across cell types untested at the time"]},{"year":2017,"claim":"Demonstrated ACSS2's role as a biosynthetic supplier in pathological lipogenesis, establishing that glucose-derived acetate routed through ACSS2 fuels viral-induced lipid synthesis.","evidence":"CRISPR/Cas9 ACSS2 KO human fibroblasts with 13C tracing and HCMV viral growth/lipogenesis readouts","pmids":["28167750"],"confidence":"High","gaps":["Did not address nuclear/epigenetic role in this context","Source of acetate generalizability beyond infection unclear"]},{"year":2018,"claim":"Defined ACSS2's systemic physiological function in lipid handling, showing it promotes fat storage, intestinal lipid absorption, and adipose-to-liver triglyceride repartitioning.","evidence":"ACSS2 KO mice under diet-induced obesity with gene expression profiling and lipid absorption assays","pmids":["30228117"],"confidence":"High","gaps":["Tissue-autonomous vs systemic contributions not separated","Mechanism linking ACSS2 to lipid transporter gene expression not detailed"]},{"year":2018,"claim":"Proposed that ACSS2 can supply non-acetyl acyl-CoA (crotonyl-CoA) to reprogram chromatin, extending its substrate scope to histone crotonylation at the HIV LTR.","evidence":"siRNA/pharmacological inhibition with ChIP for crotonylation/acetylation marks and SIV non-human primate model","pmids":["29457784"],"confidence":"Medium","gaps":["Direct crotonyl-CoA synthesis by ACSS2 not biochemically reconstituted and later contradicted in vitro","Acyltransferase partner not defined"]},{"year":2022,"claim":"Identified post-translational control of ACSS2 stability, showing OGT–CDK5 phosphorylation at S267 blocks ubiquitination to sustain acetate-to-acetyl-CoA flux and lipogenesis.","evidence":"CDK5 kinase assay, S267 phospho-mutants, ubiquitination assay, OGT manipulation, and in vivo GBM growth","pmids":["35190642"],"confidence":"High","gaps":["E3 ligase mediating ACSS2 ubiquitination not identified","Link between S267 status and nuclear translocation not fully connected here"]},{"year":2023,"claim":"Clarified ACSS2's conditional importance, showing it provides a compensatory acetate-dependent acetyl-CoA route for histone acetylation and chromatin accessibility only when ACLY is lost in CD8 T cells.","evidence":"Conditional ACLY/ACSS2 KO in CD8 T cells with 13C acetate tracing, ATAC-seq, histone acetylation ChIP, and infection models","pmids":["39150482"],"confidence":"High","gaps":["Determinants of substrate-source preference between ACLY and ACSS2 not defined","Quantitative threshold of acetate availability unaddressed"]},{"year":2024,"claim":"Resolved the long-debated acyl-CoA substrate specificity, demonstrating with purified enzyme that ACSS2 is restricted to acetate and cannot generate butyryl-CoA or crotonyl-CoA, directly conflicting with cellular acylation claims.","evidence":"Direct in vitro enzymatic assays with purified/recombinant ACSS2 plus structural analysis","pmids":["38369012"],"confidence":"High","gaps":["Does not explain cellular observations of non-acetyl acylation attributed to ACSS2","Possible indirect routing or partner enzymes not tested"]},{"year":2024,"claim":"Identified ACSS2 as a lactyl-CoA synthetase coupling lactate to histone lactylation, defining a structurally validated metabolite-supply mechanism for an acyltransferase partner.","evidence":"In vitro lactyl-CoA synthetase assay, co-crystal structure of lactyl-CoA–KAT2A, ERK/S267 phospho assays, Co-IP, ChIP, and brain tumor models","pmids":["39561764"],"confidence":"High","gaps":["Relative cellular abundance of lactyl-CoA vs acetyl-CoA flux not quantified","Reconciliation with strict acetate-only in vitro specificity not addressed"]},{"year":2024,"claim":"Expanded ACSS2's nuclear partner repertoire to transcription-factor acetylation, showing it acetylates SP1 (K19) to stabilize it and drive the SP1–SAT1 polyamine axis enabling cancer survival under acidosis.","evidence":"H3K27ac ChIP-seq, RNA-seq, ACSS2–SP1 Co-IP, mass spectrometry of SP1 K19ac, and mouse tumor models","pmids":["38429478"],"confidence":"High","gaps":["Whether ACSS2 acetylates SP1 directly or via a recruited acyltransferase unclear","Generality beyond pancreatic cancer untested"]},{"year":2024,"claim":"Linked ACSS2-driven de novo lipogenesis to programmed cell death, showing ACSS2 promotes NADPH depletion, ROS, and NLRP3-dependent pyroptosis driving kidney fibrosis.","evidence":"ACSS2 KO mice across fibrosis models, primary tubular cells, NADPH/ROS measurement, and NLRP3/FASN pharmacology","pmids":["38051585"],"confidence":"High","gaps":["Nuclear vs cytosolic ACSS2 contribution to this phenotype not separated","Upstream regulators of ACSS2 in tubular cells undefined"]},{"year":2025,"claim":"Identified ACSS2 as a β-hydroxybutyryl-CoA synthetase coupling ketone metabolism to epigenetics by supplying BHB-CoA to KAT7 for H3K9bhb.","evidence":"In vitro BHB-CoA synthetase assay, mass spectrometry of Kbhb substrates, ACSS2–KAT7 Co-IP, chromatin co-localization, and ChIP","pmids":["40815653"],"confidence":"High","gaps":["In vivo physiological importance of the ACSS2–KAT7 axis not established","Reconciliation with acetate-only in vitro specificity not addressed"]},{"year":2025,"claim":"Defined degradative regulation of ACSS2 under amino acid stress, showing SIRT2 deacetylation of K271 licenses ubiquitination and degradation to suppress lipogenesis.","evidence":"In vitro SIRT2 deacetylation assay, K271 mutagenesis, ubiquitination assay, and lipogenesis measurement under nutrient stress","pmids":["40331334"],"confidence":"High","gaps":["E3 ligase acting on K271 not identified","Interplay between K271 acetylation and S267 phosphorylation not mapped"]},{"year":2026,"claim":"Demonstrated ACSS2's role in myelination and aging, showing it drives H4K12/H3K27 acetylation of Gria2 to maintain oligodendrocyte progenitor proliferation, with acetate supplementation rescuing remyelination.","evidence":"OPC-lineage ACSS2 KO mice, ChIP at the Gria2 locus, acetate supplementation rescue, and myelin/cognition assays","pmids":["41781676"],"confidence":"High","gaps":["Acyltransferase partner at the Gria2 locus not defined","Direct nuclear localization in OPCs not shown"]},{"year":null,"claim":"It remains unresolved how ACSS2, biochemically restricted to acetate in purified-enzyme reconstitution, is reported to generate lactyl-CoA, BHB-CoA, and crotonyl-CoA in cellular contexts, and what governs its choice of acyltransferase partner at specific loci.","evidence":"Open question arising from the conflict between in vitro substrate-specificity data and cellular acylation studies","pmids":[],"confidence":"Low","gaps":["No unified structural/biochemical model reconciles acetate-only specificity with multi-acyl-CoA cellular claims","Rules determining which acyltransferase ACSS2 partners with at a given promoter are unknown","E3 ligases governing ACSS2 turnover not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[5,1,2]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13,3,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,6,13,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,6,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,15]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,0,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,28,30]}],"complexes":[],"partners":["TFEB","KAT2A","KAT7","CBP","SP1","PPARG","KPNA1","HMGCS1"],"other_free_text":[]}},"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 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40729863","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51714,"output_tokens":9773,"usd":0.150868,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20331,"output_tokens":5271,"usd":0.116715,"stage2_stop_reason":"end_turn"},"total_usd":0.267583,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, exposing a nuclear localization signal that binds importin α5 (KPNA1), enabling nuclear translocation. In the nucleus, ACSS2 forms a complex with transcription factor EB (TFEB) at lysosomal and autophagy gene promoters, where it locally converts acetate (derived from histone deacetylation turnover) to acetyl-CoA to support histone H3 acetylation at these loci, promoting lysosomal biogenesis and autophagy.\",\n      \"method\": \"AMPK kinase assay, phospho-site mutagenesis (S659A knock-in), co-immunoprecipitation (ACSS2–importin α5, ACSS2–TFEB), ChIP-seq at lysosomal/autophagy gene promoters, nuclear fractionation, glioblastoma cell and mouse brain tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phospho-site mutagenesis, reconstituted nuclear translocation mechanism, ChIP-seq, reciprocal Co-IP, functional rescue with multiple mutant knock-ins in cells and in vivo; replicated in companion Autophagy paper (PMID:28820290)\",\n      \"pmids\": [\"28552616\", \"28820290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGFR activation drives ERK-mediated phosphorylation of ACSS2 at S267, promoting its nuclear translocation and complex formation with lysine acetyltransferase KAT2A. ACSS2 functions as a bona fide lactyl-CoA synthetase, converting lactate to lactyl-CoA; co-crystal structure shows lactyl-CoA bound to KAT2A, which then acts as a lactyltransferase to lactylate histone H3, driving Wnt/β-catenin, NF-κB, and PD-L1 expression.\",\n      \"method\": \"In vitro lactyl-CoA synthetase assay with purified ACSS2, co-crystal structure of lactyl-CoA–KAT2A complex, ERK phosphorylation assay, Co-IP (ACSS2–KAT2A), ChIP, S267 mutagenesis, interaction-blocking peptide experiments, mouse brain tumor models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic reconstitution in vitro, co-crystal structure with functional validation, phospho-site mutagenesis, reciprocal Co-IP, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"39561764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 functions as a β-hydroxybutyryl-CoA (BHB-CoA) synthetase by converting β-hydroxybutyrate to BHB-CoA in the nucleus, where it co-localizes with lysine acetyltransferase KAT7. KAT7 acts as a β-hydroxybutyryltransferase that preferentially catalyzes histone H3K9 β-hydroxybutyrylation (H3K9bhb) using ACSS2-generated BHB-CoA, linking ketone metabolism to epigenetic transcriptional activation.\",\n      \"method\": \"In vitro BHB-CoA synthetase assay with purified ACSS2, mass spectrometry identification of 1171 Kbhb substrates, Co-IP (ACSS2–KAT7), chromatin co-localization, ChIP, KAT7 acetyltransferase assays, nuclear fractionation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic reconstitution, Co-IP, ChIP, mass spectrometry; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40815653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 directly interacts with and promotes acetylation of PAICS (a key purine biosynthesis enzyme) at the K site; this acetylation triggers autophagy-mediated PAICS degradation, limiting purine metabolism and dNTP pools, which exacerbates cytoplasmic chromatin fragment accumulation and the senescence-associated secretory phenotype (SASP).\",\n      \"method\": \"Co-IP (ACSS2–PAICS), acetylation site mutagenesis, autophagy flux assays, dNTP pool measurement, Acss2 KO mouse model, pharmacological ACSS2 inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, genetic KO in mice with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"40021646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACSS2 produces crotonyl-CoA (from crotonate), and its increased expression reprograms chromatin at the HIV LTR through histone crotonylation, raising histone acetylation and reducing histone methylation to reactivate latent HIV. siRNA knockdown or pharmacological inhibition of ACSS2 diminishes histone crotonylation-induced HIV reactivation.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, ChIP at HIV LTR (histone crotonylation/acetylation/methylation marks), latent HIV reactivation assay, SIV-infected non-human primate model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, siRNA/pharmacological inhibition, in vivo NHP model; single lab; note: subsequent in vitro study (PMID:38369012) shows ACSS2 does NOT generate crotonyl-CoA from crotonate, creating a direct conflict — confidence lowered accordingly\",\n      \"pmids\": [\"29457784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vitro experiments with purified/recombinant ACSS2 demonstrate that ACSS2 is UNABLE to generate butyryl-CoA or crotonyl-CoA from butyrate or crotonate; ACSS2 activity is restricted to acetyl-CoA synthesis from acetate.\",\n      \"method\": \"Direct in vitro enzymatic assay with purified and recombinant ACSS2, structural analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified enzyme plus structural considerations; single lab but definitive biochemical result contradicting prior claims\",\n      \"pmids\": [\"38369012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ACSS2 is required for acetylation of HIF-2α by the acetyltransferase CBP (CREB-binding protein) during hypoxia and glucose deprivation; acetate levels increase during stress and coincide with maximal HIF-2α acetylation and stable CBP/HIF-2α complex formation. ACSS2 translocates from cytosol to nucleus under stress.\",\n      \"method\": \"Co-immunoprecipitation (CBP–HIF-2α), acetylation assays, nuclear fractionation, ACSS2/HIF-2 siRNA knockdown, colony formation/migration/invasion assays, flank tumor mouse model with exogenous acetate\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, nuclear fractionation, siRNA depletion, in vivo mouse model; single lab, replicated in follow-up papers (PMID:29281714, PMID:36862715)\",\n      \"pmids\": [\"25689462\", \"29281714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"O-GlcNAc transferase (OGT) regulates ACSS2 stability by promoting CDK5-dependent phosphorylation of ACSS2 at Ser-267, which reduces ACSS2 polyubiquitination and proteasomal degradation, thereby increasing acetate-to-acetyl-CoA conversion and lipid production in glioblastoma cells.\",\n      \"method\": \"CDK5 kinase assay, S267 phospho-mimetic/phospho-null mutagenesis, ubiquitination assay, OGT overexpression/inhibition, Co-IP, in vitro and in vivo GBM growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phospho-site mutagenesis, ubiquitination assay, kinase assay, in vivo rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35190642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under amino acid deficiency, SIRT2 deacetylates ACSS2 at lysine K271, which promotes K271 ubiquitination and subsequent proteasomal degradation of ACSS2, suppressing de novo lipogenesis. Substitution of K271 decreases ubiquitination, stabilizes ACSS2, and increases lipogenesis.\",\n      \"method\": \"SIRT2 deacetylation assay in vitro, K271 mutagenesis, ubiquitination assay, lipogenesis measurement, nutrient-stress cell culture experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro deacetylation assay, site-directed mutagenesis, ubiquitination assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40331334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mice lacking ACSS2 show reduced body weight and hepatic steatosis under diet-induced obesity, with reduced intestinal lipid absorption and impaired repartitioning of triglycerides from adipose tissue to liver due to lowered expression of lipid transporters and fatty acid oxidation genes, demonstrating that ACSS2 promotes systemic fat storage and utilization through selective regulation of lipid metabolism genes.\",\n      \"method\": \"ACSS2 knockout mice, diet-induced obesity model, gene expression profiling, body composition analysis, lipid absorption assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with clear phenotypic readout in multiple metabolic parameters; single lab but in vivo with rigorous controls\",\n      \"pmids\": [\"30228117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus (HCMV)-induced lipogenesis and viral growth; ACSS2-KO human fibroblasts (via CRISPR/Cas9) exhibit sharply reduced HCMV-induced lipogenesis and viral replication. Glucose-derived acetate (produced non-enzymatically from pyruvate) is the substrate used by ACSS2 in HCMV-infected cells.\",\n      \"method\": \"CRISPR/Cas9 ACSS2 knockout human fibroblasts, 13C isotope tracing, viral growth assays, lipogenesis measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CRISPR KO with isotope tracing and functional viral growth readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28167750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A transition-state mimetic small-molecule inhibitor of ACSS2 blocks ACSS2 enzymatic activity in vitro and in vivo, impairing breast tumor growth as a single agent, validating ACSS2 as a druggable acetate-to-acetyl-CoA enzyme in cancer.\",\n      \"method\": \"In vitro ACSS2 enzyme inhibition assay, cell viability assays, mouse xenograft tumor model with pharmacologic ACSS2 inhibitor\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with inhibitor, in vivo tumor model; single lab but transition-state mimetic provides mechanistic evidence of enzymatic targeting\",\n      \"pmids\": [\"33414169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SREBP-1 directly regulates ACSS2 gene transcription by binding to a sterol response element (SRE) at −475 to −483 bp on the ACSS2 promoter, as shown by luciferase reporter assay and SREBP-1 interaction with the SRE site.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown of ACSS2 and ACLY, RT-qPCR, lipid droplet quantification\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase reporter with SRE mutagenesis and siRNA knockdown; single lab\",\n      \"pmids\": [\"28407230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 channels stroma-derived acetate into epigenetic regulation in pancreatic cancer cells, mediating acetylation of the transcription factor SP1 at lysine 19 residue, increasing SP1 protein stability and transcriptional activity. This promotes SAT1 gene expression via the ACSS2-SP1-SAT1 axis, altering polyamine homeostasis and enabling cancer cell survival under acidosis.\",\n      \"method\": \"H3K27ac ChIP-seq, RNA-seq, Co-IP (ACSS2–SP1), mass spectrometry (SP1 K19 acetylation), siRNA/pharmacological inhibition, mouse tumor models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq, mass spectrometry acetylation site identification, Co-IP, in vivo tumor models; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38429478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 regulates de novo lipogenesis (DNL) in kidney tubular cells, causing NADPH depletion and increased ROS levels, ultimately leading to NLRP3-dependent pyroptosis. ACSS2-KO mice are protected from kidney fibrosis in multiple disease models.\",\n      \"method\": \"ACSS2 KO mice, primary tubular cell cultures, NADPH/ROS measurement, NLRP3 inhibition, pharmacological inhibition of fatty acid synthase, DNL flux assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, multiple disease models, mechanistic pathway dissection with pharmacological controls; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38051585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Alternative transcription start site selection of ACSS2 produces two isoforms (ACSS2-S1 and ACSS2-S2) with different subcellular localizations: ACSS2-S1 localizes predominantly to the cytoplasm while ACSS2-S2 distributes to both nucleus and cytoplasm. Only ACSS2-S2 overexpression promotes HCC cell proliferation and invasion, correlating with enhanced ribosome biogenesis.\",\n      \"method\": \"Alternative TSS analysis, subcellular fractionation, overexpression of individual isoforms, cell proliferation and invasion assays, ribosome biogenesis analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fractionation plus functional overexpression assays with two isoforms; single lab\",\n      \"pmids\": [\"31076106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 inhibition in clear cell RCC reduces HIF-2α protein levels and stability through a pVHL-independent pathway involving the E3 ligase MUL1, which directly interacts with HIF-2α; ACSS2 inhibition decreases chromatin accessibility at the HIF-2α locus, reducing HIF-2α expression and suppressing ccRCC growth.\",\n      \"method\": \"ACSS2 pharmacological inhibition, MUL1 Co-IP with HIF-2α, MUL1 overexpression (HIF-2α level reduction), ATAC-seq (chromatin accessibility), primary patient tumor cultures, in vivo ccRCC models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP (MUL1–HIF-2α), ATAC-seq, primary patient tumor models; single lab, pathway not fully reconstituted\",\n      \"pmids\": [\"38941296\"],\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, recruiting SIRT1 and PRDM16 to activate UCP1 expression. SIRT1 then deacetylates PPARγ and triggers ACSS2 translocation from PPARγ to P300, inducing PPARγ polyubiquitination and degradation, thereby coupling PPARγ activation with its degradation to enhance adipose tissue plasticity.\",\n      \"method\": \"Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), PPARγ acetylation/ubiquitination assays, ACSS2 KO and overexpression in mice, UCP1/thermogenesis readouts\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, in vivo mouse model; single lab\",\n      \"pmids\": [\"38332049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In CD8 T cells, ACSS2 provides an alternative acetate-dependent pathway for cytosolic acetyl-CoA production when ACLY is ablated. ACSS2-derived acetyl-CoA supports histone acetylation and chromatin accessibility at effector gene loci, maintaining CD8 T cell effector function. When ACLY is functional, ACSS2 is not required for this process.\",\n      \"method\": \"Conditional ACLY and/or ACSS2 KO in CD8 T cells, infection models, ATAC-seq, 13C acetate tracing, histone acetylation ChIP\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional double KO, isotope tracing, ATAC-seq, infection model with functional readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39150482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSS2 promotes alkaliptosis in pancreatic cancer cells by producing acetyl-CoA that supports histone acetylation contributing to NF-κB-dependent downregulation of carbonic anhydrase 9 (CA9). ACSS2 knockdown blocks JTC801-induced alkaliptosis and NF-κB-mediated CA9 downregulation.\",\n      \"method\": \"shRNA knockdown, qPCR, western blot, cell death assays, histone deacetylase inhibitor (TSA) combination, ACSS2 knockdown + NF-κB reporter\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA/shRNA with mechanistic follow-up; single lab, limited reconstitution\",\n      \"pmids\": [\"36707625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Alcohol downregulates hepatic ACSS2, leading to acetate accumulation. ACSS2 binds CREB-binding protein (CBP) to mediate histone acetylation and regulate hepcidin (HAMP1/2) transcription; ACSS2 deficiency downregulates HAMP1/2, causing iron dyshomeostasis and ferroptosis in alcoholic liver disease. Overexpression of HAMP1/2 rescues the ferroptosis phenotype caused by ACSS2 deficiency.\",\n      \"method\": \"Co-IP (ACSS2–CBP), ChIP (H3K27ac at HAMP1/2 promoters), ACSS2 KO mice, HAMP1/2 rescue overexpression, iron chelator/ferroptosis inhibitor treatment, alcohol-fed mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, genetic KO with rescue experiment, in vivo mouse model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40593779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alcohol metabolism promotes nuclear translocation of ACSS2 in hepatocytes; nuclear ACSS2 supports acetyl-CoA production for H3K9 acetylation at lipogenic gene (Fasn, Acaca) promoters via PCAF (but not GCN5, CBP, or p300), driving de novo lipogenesis and hepatic steatosis. Liver-specific ACSS2 knockdown blocks PCAF–H3K9 interaction and suppresses lipogenic gene induction.\",\n      \"method\": \"Nuclear fractionation, CUT&RUN (H3K9ac at promoters), Co-IP (PCAF–H3K9ac), liver-specific ACSS2 knockdown mice, ethanol/acetate treatment of hepatocytes\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — CUT&RUN, Co-IP, liver-specific KD in vivo; single lab\",\n      \"pmids\": [\"37183518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 inhibition triggers its nuclear translocation (under glycolytic inhibition context), increasing SIRT1 expression; nuclear SIRT1 then deacetylates ATG5 and ATG2B, activating autophagy in ovarian cancer cells. ACSS2 inhibition also suppresses HXK2-dependent glycolysis.\",\n      \"method\": \"CUT&TAG, Co-IP, ACSS2 knockdown, SIRT1 inhibitor experiments, autophagy flux assays, ATG5/ATG2B acetylation analysis, Seahorse metabolic assay\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — CUT&TAG, Co-IP, multiple functional assays; single lab\",\n      \"pmids\": [\"39362518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 interacts with HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) in pancreatic neuroendocrine neoplasms as shown by Co-IP; ACSS2 regulates lipid metabolism reprogramming and activates the PI3K/AKT/mTOR pathway. HMGCS1 overexpression reverses the effects of ACSS2 knockdown on lipid metabolism and PI3K/AKT/mTOR pathway.\",\n      \"method\": \"Co-IP (ACSS2–HMGCS1), siRNA knockdown, HMGCS1 overexpression rescue, lipid metabolism assays, PI3K/AKT/mTOR pathway analysis, xenograft mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional rescue experiments; single lab\",\n      \"pmids\": [\"38263056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 binds directly to PPARγ and TFEB as obligatory mediators for their co-activation of TPH2 transcription in neurons; short-chain fatty acids (SCFAs) activate ACSS2, which promotes TPH2 promoter histone acetylation and transcription. ACSS2 nuclear translocation is required for SCFA-mediated antidepressant responses and depends on AMPK activation.\",\n      \"method\": \"Stereotaxic AAV-mediated ACSS2 knockdown in hippocampus, Co-IP (ACSS2–PPARγ, ACSS2–TFEB), ChIP (H3ac at TPH2 promoter), behavioral assays, AMPK inhibitor experiments\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ChIP, in vivo AAV knockdown with behavioral readout; single lab\",\n      \"pmids\": [\"38939042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 mediates H4K12 acetylation and H3K27 acetylation in hepatic stellate cells (HSCs) under SREBP2 transcriptional control; SREBP2 directly binds the ACSS2 promoter to activate ACSS2 transcription. HSC-specific ACSS2 deletion ameliorates liver fibrosis, and ACSS2 inhibition suppresses TGFβ1-induced primary human HSC activation.\",\n      \"method\": \"CUT&Tag-seq (SREBP2 at ACSS2 promoter), RNA-seq, HSC-specific ACSS2 KO mice, ACSS2 ectopic overexpression rescue, pharmacological ACSS2 inhibition, human liver biopsy validation\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag-seq, genetic KO, human validation; single lab\",\n      \"pmids\": [\"41887397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ACSS2 mediates crotonate-to-crotonyl-CoA conversion (in this study's context via p300 as acyltransferase), and ACSS2-generated crotonyl-CoA fuels p300-catalyzed crotonylation of EZH2 at K348, leading to EZH2 ubiquitination and degradation, reducing genome-wide H3K27me3.\",\n      \"method\": \"In vitro crotonylation assay, mass spectrometry (EZH2-K348cr), Co-IP (ACSS2–p300–EZH2), H3K27me3 ChIP-seq, EZH2 ubiquitination assay, mouse breast cancer models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro assay, mass spectrometry, Co-IP, ChIP-seq; single lab; note: conflicts with PMID:38369012 showing ACSS2 cannot generate crotonyl-CoA — confidence limited\",\n      \"pmids\": [\"41544165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In oligodendrocyte progenitor cells (OPCs), ACSS2-mediated histone H4K12 and H3K27 acetylation enhances expression of Gria2 (an AMPA receptor subunit critical for OPC proliferation). Deletion of ACSS2 in the oligodendrocyte lineage reduces OPC population, impairs myelinogenesis, and exacerbates age-related cognitive deficits; acetate supplementation (ACSS2 substrate) preserves OPCs and promotes remyelination.\",\n      \"method\": \"OPC-specific ACSS2 KO mice, ChIP (H4K12ac, H3K27ac at Gria2 locus), acetate supplementation rescue, myelination assays, cognitive function tests\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lineage-specific KO, ChIP, acetate supplementation rescue, in vivo myelin and cognitive readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41781676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 inhibition in breast cancer brain metastatic cells suppresses ferroptosis via an E2F1-mediated transcriptional mechanism regulating anti-ferroptotic proteins SLC7A11 and GPX4; ACSS2-S267D phospho-mimetic is required for in vivo brain (but not mammary fat pad) tumor growth, implicating OGT/CDK5-mediated S267 phosphorylation as critical for brain-specific ACSS2 function.\",\n      \"method\": \"ACSS2 S267D phospho-mimetic expression, E2F1 ChIP at SLC7A11/GPX4 promoters, ferroptosis assays, in vivo brain vs mammary fat pad tumor growth comparison, pharmacological ACSS2 inhibitor ex vivo/in vivo\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — phospho-mimetic, ChIP, in vivo comparison; preprint, single lab\",\n      \"pmids\": [\"39484430\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 mediates β-cell adaptation to pregnancy stress by supporting acetyl-CoA biosynthesis; STAT3 recruits p300 to promote histone acetylation of pregnancy-associated genes, a process enhanced by ACSS2. β-cell-specific deletion of Acss2 rescues HFD-induced impairment of β-cell function during gestation.\",\n      \"method\": \"Single-cell transcriptomics, β-cell-specific ACSS2 KO mice, ChIP (H3ac at pregnancy-associated gene promoters), STAT3/p300 Co-IP, gestational diabetes model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO, ChIP, Co-IP, single-cell transcriptomics; single lab\",\n      \"pmids\": [\"40393969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2-mediated H3K9 crotonylation increases IL-1β expression in kidney tubular epithelial cells during fibrosis; genetic and pharmacological inhibition of ACSS2 suppresses H3K9cr-mediated IL-1β expression, alleviating IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis.\",\n      \"method\": \"ChIP-seq (H3K9cr), RNA-seq, ACSS2 KO mice, pharmacological ACSS2 inhibition, macrophage activation assay, tubular cell senescence assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, RNA-seq, genetic KO, pharmacological inhibition with specific cellular readouts; single lab; note: conflicts with PMID:38369012 (ACSS2 cannot make crotonyl-CoA) — lower confidence for the crotonylation mechanism specifically\",\n      \"pmids\": [\"38615014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acetate promotes SNAI1 expression via ACSS2-mediated histone H3K27 acetylation at the SNAI1 regulatory region under glucose limitation; ACSS2 knockdown decreases acetate-induced SNAI1 expression and cell migration, while ACSS2 overexpression increases H3K27ac and SNAI1 levels. ChIP showed increased H3K27ac at the SNAI1 locus but no increase in ACSS2 direct binding.\",\n      \"method\": \"ChIP (H3K27ac at SNAI1 locus), siRNA knockdown of ACSS2, ACSS2 overexpression, wound healing and invasion assays\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP, siRNA, overexpression; single lab\",\n      \"pmids\": [\"32458971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of ACSS2 in mice leads to tissue-specific dysregulation of canonical signaling pathways and transcription factor networks in liver, brain, and mesenteric adipose tissue, demonstrating that ACSS2 acts as a transcriptional regulatory enzyme; however, ACSS2 loss resulted in few changes in fatty acid constitution across these tissues.\",\n      \"method\": \"Acss2 KO mice, transcriptomic analysis (RNA-seq) of liver, brain, and adipose, fatty acid composition analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO transcriptomics with fatty acid measurement; single lab, descriptive mechanistic interpretation\",\n      \"pmids\": [\"36835088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Acss2 KO mice consume significantly less voluntary alcohol and exhibit blunted gene expression in the ventral striatum following drinking, associated with depletion of ventral striatal H3K27ac. This demonstrates ACSS2 is required for alcohol-derived acetate incorporation into histone acetylation marks in brain reward circuits.\",\n      \"method\": \"Acss2 KO mice, binge drinking model, genome-wide transcriptional profiling (7 brain regions), H3K27ac ChIP in ventral striatum\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, ChIP, genome-wide transcriptomics; single lab\",\n      \"pmids\": [\"39653249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 promotes temozolomide resistance in pancreatic neuroendocrine tumors by mediating acetate-to-acetyl-CoA conversion, causing histone hyperacetylation that promotes BCL6 transcription. BCL6 then binds the TP53 promoter and silences p53 expression, bypassing DNA damage-induced apoptosis.\",\n      \"method\": \"Single-cell RNA-seq, ChIP (BCL6 at TP53 promoter, H3ac at BCL6 locus), ACSS2 KI/KO, patient-derived organoids, immunocompetent Rip1-Tag2 mice, ACSS2 inhibitor + anti-PD1 combination\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, organoids, in vivo mouse model; single lab\",\n      \"pmids\": [\"41786280\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate (and β-hydroxybutyrate) to their cognate acyl-CoAs; it is regulated by AMPK-mediated S659 phosphorylation and CDK5-mediated S267 phosphorylation (stabilizing it from ubiquitination), and counter-regulated by SIRT2-mediated K271 deacetylation (promoting its degradation), while in the nucleus it binds transcription factors (TFEB, HIF-2α/CBP, KAT2A, KAT7, PPARγ, SP1, AATF) and locally regenerates acetyl-CoA or BHB-CoA from deacetylation-derived metabolites to support histone H3 acetylation, β-hydroxybutyrylation, and lactylation at specific gene promoters governing autophagy, lysosomal biogenesis, lipid metabolism, immune evasion, and stress responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate to acetyl-CoA and serves as a metabolic-epigenetic hub coupling nutrient and stress states to histone acylation and gene transcription [#5, #1]. Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, exposing a nuclear localization signal that engages importin α5 to drive nuclear translocation, where ACSS2 complexes with TFEB at lysosomal and autophagy gene promoters and locally regenerates acetyl-CoA from deacetylation-derived acetate to support promoter H3 acetylation [#1]. Its stability and localization are controlled by post-translational modification: OGT-driven CDK5 phosphorylation at S267 (and EGFR/ERK signaling at the same residue) protects ACSS2 from polyubiquitination while promoting nuclear translocation [#7, #1], whereas SIRT2 deacetylation of K271 promotes K271 ubiquitination and proteasomal degradation, suppressing lipogenesis [#8]. In the nucleus ACSS2 acts as a substrate-providing partner for diverse acyltransferases: it functions as a lactyl-CoA synthetase supplying lactyl-CoA to KAT2A for histone lactylation [#1], and as a β-hydroxybutyryl-CoA synthetase supplying BHB-CoA to KAT7 for H3K9 β-hydroxybutyrylation [#2]. Through these activities ACSS2 also directly binds transcription factors and chromatin regulators—HIF-2α/CBP [#6], SP1 [#13], PPARγ [#17], and PCAF/p300-linked complexes [#21]—to acetylate substrates and activate target loci governing immune evasion, polyamine homeostasis, adipose plasticity, and lipogenesis. At the systemic level, ACSS2 promotes de novo lipogenesis and fat storage, and its genetic loss alters lipid metabolism gene programs and protects against diet-induced steatosis, kidney fibrosis, and liver fibrosis [#9, #14, #25]. ACSS2 is enzymatically restricted to acetate in rigorous in vitro reconstitution, which conflicts with cellular reports of crotonyl-CoA, butyryl-CoA, and related acyl-CoA generation [#5, #4, #26]. A transition-state mimetic inhibitor validates ACSS2 as a druggable target in cancer [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that ACSS2 acts beyond cytosolic metabolism by translocating to the nucleus under stress to enable transcription-factor acetylation, answering whether acetate metabolism feeds nuclear signaling.\",\n      \"evidence\": \"Co-IP of CBP–HIF-2α, nuclear fractionation, and siRNA depletion with in vivo tumor model under hypoxia/glucose deprivation\",\n      \"pmids\": [\"25689462\", \"29281714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the kinase or signal triggering nuclear translocation\", \"Direct ACSS2 enzymatic activity at the locus not reconstituted\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the molecular mechanism of stress-induced nuclear targeting, showing AMPK-S659 phosphorylation unmasks an NLS for importin α5 and that nuclear ACSS2 locally regenerates acetyl-CoA at TFEB target promoters to drive autophagy/lysosomal genes.\",\n      \"evidence\": \"AMPK kinase assay, S659A knock-in, ACSS2–importin α5 and ACSS2–TFEB Co-IP, ChIP-seq in glioblastoma cells and mouse brain tumors\",\n      \"pmids\": [\"28552616\", \"28820290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of local vs bulk acetyl-CoA pools unresolved\", \"Generality of the TFEB axis across cell types untested at the time\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated ACSS2's role as a biosynthetic supplier in pathological lipogenesis, establishing that glucose-derived acetate routed through ACSS2 fuels viral-induced lipid synthesis.\",\n      \"evidence\": \"CRISPR/Cas9 ACSS2 KO human fibroblasts with 13C tracing and HCMV viral growth/lipogenesis readouts\",\n      \"pmids\": [\"28167750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address nuclear/epigenetic role in this context\", \"Source of acetate generalizability beyond infection unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined ACSS2's systemic physiological function in lipid handling, showing it promotes fat storage, intestinal lipid absorption, and adipose-to-liver triglyceride repartitioning.\",\n      \"evidence\": \"ACSS2 KO mice under diet-induced obesity with gene expression profiling and lipid absorption assays\",\n      \"pmids\": [\"30228117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-autonomous vs systemic contributions not separated\", \"Mechanism linking ACSS2 to lipid transporter gene expression not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proposed that ACSS2 can supply non-acetyl acyl-CoA (crotonyl-CoA) to reprogram chromatin, extending its substrate scope to histone crotonylation at the HIV LTR.\",\n      \"evidence\": \"siRNA/pharmacological inhibition with ChIP for crotonylation/acetylation marks and SIV non-human primate model\",\n      \"pmids\": [\"29457784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct crotonyl-CoA synthesis by ACSS2 not biochemically reconstituted and later contradicted in vitro\", \"Acyltransferase partner not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-translational control of ACSS2 stability, showing OGT–CDK5 phosphorylation at S267 blocks ubiquitination to sustain acetate-to-acetyl-CoA flux and lipogenesis.\",\n      \"evidence\": \"CDK5 kinase assay, S267 phospho-mutants, ubiquitination assay, OGT manipulation, and in vivo GBM growth\",\n      \"pmids\": [\"35190642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating ACSS2 ubiquitination not identified\", \"Link between S267 status and nuclear translocation not fully connected here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified ACSS2's conditional importance, showing it provides a compensatory acetate-dependent acetyl-CoA route for histone acetylation and chromatin accessibility only when ACLY is lost in CD8 T cells.\",\n      \"evidence\": \"Conditional ACLY/ACSS2 KO in CD8 T cells with 13C acetate tracing, ATAC-seq, histone acetylation ChIP, and infection models\",\n      \"pmids\": [\"39150482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate-source preference between ACLY and ACSS2 not defined\", \"Quantitative threshold of acetate availability unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the long-debated acyl-CoA substrate specificity, demonstrating with purified enzyme that ACSS2 is restricted to acetate and cannot generate butyryl-CoA or crotonyl-CoA, directly conflicting with cellular acylation claims.\",\n      \"evidence\": \"Direct in vitro enzymatic assays with purified/recombinant ACSS2 plus structural analysis\",\n      \"pmids\": [\"38369012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain cellular observations of non-acetyl acylation attributed to ACSS2\", \"Possible indirect routing or partner enzymes not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ACSS2 as a lactyl-CoA synthetase coupling lactate to histone lactylation, defining a structurally validated metabolite-supply mechanism for an acyltransferase partner.\",\n      \"evidence\": \"In vitro lactyl-CoA synthetase assay, co-crystal structure of lactyl-CoA–KAT2A, ERK/S267 phospho assays, Co-IP, ChIP, and brain tumor models\",\n      \"pmids\": [\"39561764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative cellular abundance of lactyl-CoA vs acetyl-CoA flux not quantified\", \"Reconciliation with strict acetate-only in vitro specificity not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded ACSS2's nuclear partner repertoire to transcription-factor acetylation, showing it acetylates SP1 (K19) to stabilize it and drive the SP1–SAT1 polyamine axis enabling cancer survival under acidosis.\",\n      \"evidence\": \"H3K27ac ChIP-seq, RNA-seq, ACSS2–SP1 Co-IP, mass spectrometry of SP1 K19ac, and mouse tumor models\",\n      \"pmids\": [\"38429478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACSS2 acetylates SP1 directly or via a recruited acyltransferase unclear\", \"Generality beyond pancreatic cancer untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ACSS2-driven de novo lipogenesis to programmed cell death, showing ACSS2 promotes NADPH depletion, ROS, and NLRP3-dependent pyroptosis driving kidney fibrosis.\",\n      \"evidence\": \"ACSS2 KO mice across fibrosis models, primary tubular cells, NADPH/ROS measurement, and NLRP3/FASN pharmacology\",\n      \"pmids\": [\"38051585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear vs cytosolic ACSS2 contribution to this phenotype not separated\", \"Upstream regulators of ACSS2 in tubular cells undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ACSS2 as a β-hydroxybutyryl-CoA synthetase coupling ketone metabolism to epigenetics by supplying BHB-CoA to KAT7 for H3K9bhb.\",\n      \"evidence\": \"In vitro BHB-CoA synthetase assay, mass spectrometry of Kbhb substrates, ACSS2–KAT7 Co-IP, chromatin co-localization, and ChIP\",\n      \"pmids\": [\"40815653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological importance of the ACSS2–KAT7 axis not established\", \"Reconciliation with acetate-only in vitro specificity not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined degradative regulation of ACSS2 under amino acid stress, showing SIRT2 deacetylation of K271 licenses ubiquitination and degradation to suppress lipogenesis.\",\n      \"evidence\": \"In vitro SIRT2 deacetylation assay, K271 mutagenesis, ubiquitination assay, and lipogenesis measurement under nutrient stress\",\n      \"pmids\": [\"40331334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase acting on K271 not identified\", \"Interplay between K271 acetylation and S267 phosphorylation not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated ACSS2's role in myelination and aging, showing it drives H4K12/H3K27 acetylation of Gria2 to maintain oligodendrocyte progenitor proliferation, with acetate supplementation rescuing remyelination.\",\n      \"evidence\": \"OPC-lineage ACSS2 KO mice, ChIP at the Gria2 locus, acetate supplementation rescue, and myelin/cognition assays\",\n      \"pmids\": [\"41781676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acyltransferase partner at the Gria2 locus not defined\", \"Direct nuclear localization in OPCs not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ACSS2, biochemically restricted to acetate in purified-enzyme reconstitution, is reported to generate lactyl-CoA, BHB-CoA, and crotonyl-CoA in cellular contexts, and what governs its choice of acyltransferase partner at specific loci.\",\n      \"evidence\": \"Open question arising from the conflict between in vitro substrate-specificity data and cellular acylation studies\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural/biochemical model reconciles acetate-only specificity with multi-acyl-CoA cellular claims\", \"Rules determining which acyltransferase ACSS2 partners with at a given promoter are unknown\", \"E3 ligases governing ACSS2 turnover not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [5, 1, 2]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13, 3, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 6, 13, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 6, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 15]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 0, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 28, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TFEB\", \"KAT2A\", \"KAT7\", \"CBP\", \"SP1\", \"PPARG\", \"KPNA1\", \"HMGCS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}