Affinage

ACSS2

Acetyl-coenzyme A synthetase, cytoplasmic · UniProt Q9NR19

Length
701 aa
Mass
78.6 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2015 Medium

    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

    PMID:25689462 PMID:29281714

    Open questions at the time
    • Did not define the kinase or signal triggering nuclear translocation
    • Direct ACSS2 enzymatic activity at the locus not reconstituted
  2. 2017 High

    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

    PMID:28552616 PMID:28820290

    Open questions at the time
    • Quantitative contribution of local vs bulk acetyl-CoA pools unresolved
    • Generality of the TFEB axis across cell types untested at the time
  3. 2017 High

    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

    PMID:28167750

    Open questions at the time
    • Did not address nuclear/epigenetic role in this context
    • Source of acetate generalizability beyond infection unclear
  4. 2018 High

    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

    PMID:30228117

    Open questions at the time
    • Tissue-autonomous vs systemic contributions not separated
    • Mechanism linking ACSS2 to lipid transporter gene expression not detailed
  5. 2018 Medium

    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

    PMID:29457784

    Open questions at the time
    • Direct crotonyl-CoA synthesis by ACSS2 not biochemically reconstituted and later contradicted in vitro
    • Acyltransferase partner not defined
  6. 2022 High

    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

    PMID:35190642

    Open questions at the time
    • E3 ligase mediating ACSS2 ubiquitination not identified
    • Link between S267 status and nuclear translocation not fully connected here
  7. 2023 High

    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

    PMID:39150482

    Open questions at the time
    • Determinants of substrate-source preference between ACLY and ACSS2 not defined
    • Quantitative threshold of acetate availability unaddressed
  8. 2024 High

    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

    PMID:38369012

    Open questions at the time
    • Does not explain cellular observations of non-acetyl acylation attributed to ACSS2
    • Possible indirect routing or partner enzymes not tested
  9. 2024 High

    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

    PMID:39561764

    Open questions at the time
    • Relative cellular abundance of lactyl-CoA vs acetyl-CoA flux not quantified
    • Reconciliation with strict acetate-only in vitro specificity not addressed
  10. 2024 High

    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

    PMID:38429478

    Open questions at the time
    • Whether ACSS2 acetylates SP1 directly or via a recruited acyltransferase unclear
    • Generality beyond pancreatic cancer untested
  11. 2024 High

    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

    PMID:38051585

    Open questions at the time
    • Nuclear vs cytosolic ACSS2 contribution to this phenotype not separated
    • Upstream regulators of ACSS2 in tubular cells undefined
  12. 2025 High

    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

    PMID:40815653

    Open questions at the time
    • In vivo physiological importance of the ACSS2–KAT7 axis not established
    • Reconciliation with acetate-only in vitro specificity not addressed
  13. 2025 High

    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

    PMID:40331334

    Open questions at the time
    • E3 ligase acting on K271 not identified
    • Interplay between K271 acetylation and S267 phosphorylation not mapped
  14. 2026 High

    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

    PMID:41781676

    Open questions at the time
    • Acyltransferase partner at the Gria2 locus not defined
    • Direct nuclear localization in OPCs not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0016740 transferase activity 3 GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 1
Partners
CBPHMGCS1KAT2AKAT7KPNA1PPARGSP1TFEB

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 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. 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 Molecular cell High 28552616 28820290
2024 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. 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 Cell metabolism High 39561764
2025 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. 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 Science advances High 40815653
2024 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). Co-IP (ACSS2–PAICS), acetylation site mutagenesis, autophagy flux assays, dNTP pool measurement, Acss2 KO mouse model, pharmacological ACSS2 inhibition Nature communications High 40021646
2018 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. siRNA knockdown, pharmacological inhibition, ChIP at HIV LTR (histone crotonylation/acetylation/methylation marks), latent HIV reactivation assay, SIV-infected non-human primate model The Journal of clinical investigation Medium 29457784
2024 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. Direct in vitro enzymatic assay with purified and recombinant ACSS2, structural analysis Molecular metabolism High 38369012
2015 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. 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 PloS one Medium 25689462 29281714
2022 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. CDK5 kinase assay, S267 phospho-mimetic/phospho-null mutagenesis, ubiquitination assay, OGT overexpression/inhibition, Co-IP, in vitro and in vivo GBM growth assays Oncogene High 35190642
2025 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. SIRT2 deacetylation assay in vitro, K271 mutagenesis, ubiquitination assay, lipogenesis measurement, nutrient-stress cell culture experiments eLife High 40331334
2018 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. ACSS2 knockout mice, diet-induced obesity model, gene expression profiling, body composition analysis, lipid absorption assays Proceedings of the National Academy of Sciences of the United States of America High 30228117
2017 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. CRISPR/Cas9 ACSS2 knockout human fibroblasts, 13C isotope tracing, viral growth assays, lipogenesis measurement Proceedings of the National Academy of Sciences of the United States of America High 28167750
2021 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. In vitro ACSS2 enzyme inhibition assay, cell viability assays, mouse xenograft tumor model with pharmacologic ACSS2 inhibitor Cancer research High 33414169
2017 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. Luciferase reporter assay, siRNA knockdown of ACSS2 and ACLY, RT-qPCR, lipid droplet quantification Journal of cellular physiology Medium 28407230
2024 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. H3K27ac ChIP-seq, RNA-seq, Co-IP (ACSS2–SP1), mass spectrometry (SP1 K19 acetylation), siRNA/pharmacological inhibition, mouse tumor models Nature cell biology High 38429478
2024 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. ACSS2 KO mice, primary tubular cell cultures, NADPH/ROS measurement, NLRP3 inhibition, pharmacological inhibition of fatty acid synthase, DNL flux assays The Journal of clinical investigation High 38051585
2019 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. Alternative TSS analysis, subcellular fractionation, overexpression of individual isoforms, cell proliferation and invasion assays, ribosome biogenesis analysis Biochemical and biophysical research communications Medium 31076106
2024 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. 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 The Journal of clinical investigation Medium 38941296
2024 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. Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), PPARγ acetylation/ubiquitination assays, ACSS2 KO and overexpression in mice, UCP1/thermogenesis readouts Cell death and differentiation Medium 38332049
2023 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. Conditional ACLY and/or ACSS2 KO in CD8 T cells, infection models, ATAC-seq, 13C acetate tracing, histone acetylation ChIP The Journal of experimental medicine High 39150482
2023 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. shRNA knockdown, qPCR, western blot, cell death assays, histone deacetylase inhibitor (TSA) combination, ACSS2 knockdown + NF-κB reporter Scientific reports Medium 36707625
2024 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. 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 Nature communications High 40593779
2023 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. Nuclear fractionation, CUT&RUN (H3K9ac at promoters), Co-IP (PCAF–H3K9ac), liver-specific ACSS2 knockdown mice, ethanol/acetate treatment of hepatocytes Liver international Medium 37183518
2024 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. CUT&TAG, Co-IP, ACSS2 knockdown, SIRT1 inhibitor experiments, autophagy flux assays, ATG5/ATG2B acetylation analysis, Seahorse metabolic assay Metabolism: clinical and experimental Medium 39362518
2024 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. Co-IP (ACSS2–HMGCS1), siRNA knockdown, HMGCS1 overexpression rescue, lipid metabolism assays, PI3K/AKT/mTOR pathway analysis, xenograft mouse model Journal of translational medicine Medium 38263056
2024 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. Stereotaxic AAV-mediated ACSS2 knockdown in hippocampus, Co-IP (ACSS2–PPARγ, ACSS2–TFEB), ChIP (H3ac at TPH2 promoter), behavioral assays, AMPK inhibitor experiments Research (Washington, D.C.) Medium 38939042
2025 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. 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 Metabolism: clinical and experimental Medium 41887397
2026 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. In vitro crotonylation assay, mass spectrometry (EZH2-K348cr), Co-IP (ACSS2–p300–EZH2), H3K27me3 ChIP-seq, EZH2 ubiquitination assay, mouse breast cancer models Science advances Medium 41544165
2026 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. OPC-specific ACSS2 KO mice, ChIP (H4K12ac, H3K27ac at Gria2 locus), acetate supplementation rescue, myelination assays, cognitive function tests Nature aging High 41781676
2024 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. 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 bioRxivpreprint Medium 39484430
2025 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. Single-cell transcriptomics, β-cell-specific ACSS2 KO mice, ChIP (H3ac at pregnancy-associated gene promoters), STAT3/p300 Co-IP, gestational diabetes model Nature communications Medium 40393969
2024 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. ChIP-seq (H3K9cr), RNA-seq, ACSS2 KO mice, pharmacological ACSS2 inhibition, macrophage activation assay, tubular cell senescence assay Nature communications Medium 38615014
2020 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. ChIP (H3K27ac at SNAI1 locus), siRNA knockdown of ACSS2, ACSS2 overexpression, wound healing and invasion assays Bioscience reports Medium 32458971
2023 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. Acss2 KO mice, transcriptomic analysis (RNA-seq) of liver, brain, and adipose, fatty acid composition analysis International journal of molecular sciences Medium 36835088
2024 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. Acss2 KO mice, binge drinking model, genome-wide transcriptional profiling (7 brain regions), H3K27ac ChIP in ventral striatum Neuropharmacology Medium 39653249
2025 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. 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 Cancer letters Medium 41786280

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Molecular cell 296 28552616
2024 ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion. Cell metabolism 199 39561764
2018 ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proceedings of the National Academy of Sciences of the United States of America 136 30228117
2018 HIV latency is reversed by ACSS2-driven histone crotonylation. The Journal of clinical investigation 134 29457784
2006 Control of acetyl-coenzyme A synthetase (AcsA) activity by acetylation/deacetylation without NAD(+) involvement in Bacillus subtilis. Journal of bacteriology 123 16855235
2020 Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis - Part 2: Acetate and ACSS2 in Health and Disease. Frontiers in physiology 97 33304273
2017 Acyl-CoA synthetase short-chain family member 2 (ACSS2) is regulated by SREBP-1 and plays a role in fatty acid synthesis in caprine mammary epithelial cells. Journal of cellular physiology 90 28407230
2024 Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence. Nature communications 84 38615014
2021 Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth. Cancer research 81 33414169
2017 Anti-ACSA-2 defines a novel monoclonal antibody for prospective isolation of living neonatal and adult astrocytes. Glia 80 28317180
2017 An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targeting by the ACSA-2 antibody. The Journal of biological chemistry 76 28373281
2024 Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. Nature cell biology 72 38429478
2017 Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy 71 28820290
2023 ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease. Molecular neurodegeneration 69 37438762
2017 ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus infection. Proceedings of the National Academy of Sciences of the United States of America 67 28167750
2015 The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PloS one 62 25689462
2024 Sodium butyrate alleviates lead-induced neuroinflammation and improves cognitive and memory impairment through the ACSS2/H3K9ac/BDNF pathway. Environment international 60 38340407
2022 Acetyl-CoA synthetase 2(ACSS2): a review with a focus on metabolism and tumor development. Discover oncology 59 35798917
2022 O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation. Oncogene 50 35190642
2006 Sirtuins: a conserved key unlocking AceCS activity. Trends in biochemical sciences 47 17141505
2008 Biochemical and mutational analyses of AcuA, the acetyltransferase enzyme that controls the activity of the acetyl coenzyme a synthetase (AcsA) in Bacillus subtilis. Journal of bacteriology 45 18487328
1998 Expression of the Bacillus subtilis acsA gene: position and sequence context affect cre-mediated carbon catabolite repression. Journal of bacteriology 45 9852010
2021 Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy. Environmental pollution (Barking, Essex : 1987) 42 33486244
2024 Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms. Journal of translational medicine 41 38263056
2018 Glucose-derived acetate and ACSS2 as key players in cisplatin resistance in bladder cancer. Biochimica et biophysica acta. Molecular and cell biology of lipids 39 29883801
2023 ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules. The Journal of clinical investigation 38 38051585
2017 Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells. PloS one 34 29281714
2023 ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells. Scientific reports 32 36707625
2024 ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. The Journal of experimental medicine 28 39150482
2024 Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer. Metabolism: clinical and experimental 26 39362518
2022 Acetyl-CoA synthetases ACSS1 and ACSS2 are 4-hydroxytamoxifen responsive factors that promote survival in tamoxifen treated and estrogen deprived cells. Translational oncology 26 35263700
2020 Acetate promotes SNAI1 expression by ACSS2-mediated histone acetylation under glucose limitation in renal cell carcinoma cell. Bioscience reports 26 32458971
2001 The Pseudomonas aeruginosa acsA gene, encoding an acetyl-CoA synthetase, is essential for growth on ethanol. Microbiology (Reading, England) 26 11577146
2024 ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity. Cell death and differentiation 22 38332049
2024 Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells. Frontiers in pharmacology 20 38818373
2024 HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma. The Journal of clinical investigation 20 38941296
2010 Transcriptional regulation of the acetyl-CoA synthetase gene acsA in Pseudomonas aeruginosa. Archives of microbiology 19 20549193
2021 Rapamycin antagonizes cadmium-induced breast cancer cell proliferation and metastasis through directly modulating ACSS2. Ecotoxicology and environmental safety 16 34411822
2025 ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation. Nature communications 15 40021646
2004 Improvement of cotton fiber quality by transforming the acsA and acsB genes into Gossypium hirsutum L. by means of vacuum infiltration. Plant cell reports 15 14740167
2023 Acss2/HIF-2 signaling facilitates colon cancer growth and metastasis. PloS one 14 36862715
2023 Inhibition of ACSS2 attenuates alcoholic liver steatosis via epigenetically regulating de novo lipogenesis. Liver international : official journal of the International Association for the Study of the Liver 14 37183518
2023 High-fat diet-induced gut microbiota alteration promotes lipogenesis by butyric acid/miR-204/ACSS2 axis in chickens. Poultry science 14 37390560
2021 hsa-miR-15b-5p regulates the proliferation and apoptosis of human vascular smooth muscle cells by targeting the ACSS2/PTGS2 axis. Experimental and therapeutic medicine 14 34584553
2020 Mir-193b Regulates the Differentiation, Proliferation, and Apoptosis of Bovine Adipose Cells by Targeting the ACSS2/AKT Axis. Animals : an open access journal from MDPI 14 32722316
2020 NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on esophageal squamous cell carcinoma. The Biochemical journal 14 32776152
2019 ACSS2/AMPK/PCNA pathway‑driven proliferation and chemoresistance of esophageal squamous carcinoma cells under nutrient stress. Molecular medicine reports 13 31638228
2025 Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacological research 12 40127788
2024 Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis. Research (Washington, D.C.) 12 38939042
2021 ACSA-2 and GLAST classify subpopulations of multipotent and glial-restricted cerebellar precursors. Journal of neuroscience research 12 34060113
2015 AcsA-AcsB: The core of the cellulose synthase complex from Gluconacetobacter hansenii ATCC23769. Enzyme and microbial technology 12 26672449
2019 Alternative transcription start site selection in ACSS2 controls its nuclear localization and promotes ribosome biosynthesis in hepatocellular carcinoma. Biochemical and biophysical research communications 11 31076106
2018 GntR Family Regulator DasR Controls Acetate Assimilation by Directly Repressing the acsA Gene in Saccharopolyspora erythraea. Journal of bacteriology 11 29686136
2025 ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression. Nature communications 10 40593779
2024 N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation. American journal of physiology. Gastrointestinal and liver physiology 10 38591127
2019 miR-30a-GNG2 and miR-15b-ACSS2 Interaction Pairs May Be Potentially Crucial for Development of Abdominal Aortic Aneurysm by Influencing Inflammation. DNA and cell biology 10 31730405
2025 ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target. Lipids in health and disease 9 40001058
2019 ACSS2-related autophagy has a dual impact on memory. Chinese neurosurgical journal 9 32922914
2024 Acetyl-CoA synthetase (ACSS2) does not generate butyryl- and crotonyl-CoA. Molecular metabolism 8 38369012
2024 D-arabinose acts as antidepressant by activating the ACSS2-PPARγ/TFEB axis and CRTC1 transcription. Pharmacological research 8 38460778
2024 Gut microbiota regulates hepatic ischemia-reperfusion injury-induced cognitive dysfunction via the HDAC2-ACSS2 axis in mice. CNS neuroscience & therapeutics 7 38334013
2023 D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels. Translational psychiatry 7 37914710
2019 Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation. Alcoholism, clinical and experimental research 7 31283017
2025 ACSS2-Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40650658
2024 Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production. Molecular metabolism 6 39304063
2023 Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation. International journal of molecular sciences 6 36835088
2025 KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation. Cell reports 5 40131933
2025 ACSS2 coupled with KAT7 regulates histone β-hydroxybutyrylation to enhance transcription. Science advances 5 40815653
2024 miR-4443 Contained Extracellular Vesicles: A Factor for Endometriosis Progression by PI3K/AKT/ACSS2 Cascade in-vitro. International journal of nanomedicine 5 38911502
2025 SIRT2-mediated ACSS2 K271 deacetylation suppresses lipogenesis under nutrient stress. eLife 4 40331334
2025 ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice. Nature communications 4 40393969
2024 ACSS2 enables melanoma cell survival and tumor metastasis by negatively regulating the Hippo pathway. Frontiers in molecular biosciences 4 38887280
2024 Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice. Neuropharmacology 4 39653249
2025 ACSS2/AATF Drives Soluble FasL-Mediated CD8+ T Cell Apoptosis in Pancreatic Neuroendocrine Tumors. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40791180
2024 Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia. Cancer gene therapy 3 38851813
2019 [Knockdown of ACSS2 inhibits invasion and migration of cervical cancer cells induced by nutrient stress and its mechanism]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 3 31814569
2017 ACSS2 gene variant associated with cleft lip and palate in two independent Hispanic populations. The Laryngoscope 3 28543373
2017 Possible involvement of ACSS2 gene in alcoholism. Journal of neural transmission (Vienna, Austria : 1996) 3 28550509
2026 Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH. Cell metabolism 2 41500198
2026 ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America 2 41512015
2026 Multiomic single nuclei profiling the mouse hippocampus reveals that ACSS2 confers neuronal resilience to tauopathy. Alzheimer's & dementia : the journal of the Alzheimer's Association 2 41685522
2025 High fructose promotes MYCN-amplified neuroblastoma progression through NgBR-ACSS2-mediated biosynthesis of acetyl-CoA. Cell reports 2 40616844
2025 ACSS2-TFEB axis acts as a critical regulator of the autophagic machinery in head and neck squamous cell carcinoma. Cell death & disease 2 40858538
2025 Asiatic acid inhibits endothelial-to-mesenchymal transition in diabetic kidney disease by reducing acetyl-CoA production via targeting ACSS2. Biochemical pharmacology 2 40921220
2023 Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth. bioRxiv : the preprint server for biology 2 38187734
2016 Leucine-684: A conserved residue of an AMP-acetyl CoA synthetase (AceCS) from Leishmania donovani is involved in substrate recognition, catalysis and acetylation. Gene 2 26794803
2026 SREBP2 links ACSS2-dependent acetyl-CoA biosynthesis to metaboloepigenetic activation of hepatic stellate cells and liver fibrosis. Metabolism: clinical and experimental 1 41887397
2025 An Oncolytic Vaccinia Virus Expressing Aphrocallistes Vastus Lectin Modulates Hepatocellular Carcinoma Metabolism via ACSS2/TFEB-Mediated Autophagy and Lipid Accumulation. Marine drugs 1 40863614
2025 The ACSS2-PPARD-BCAT1 axis synchronously regulates branched-chain amino acid metabolism and development in pancreatic cancer. Acta biochimica et biophysica Sinica 1 40908872
2025 Focused ultrasound-induced blood-brain barrier opening promotes glioprotective phenotypes in ACSA-II+ murine astrocytes. iScience 1 40948563
2025 ACSS2-Mediated Metabolic-Epigenetic Crosstalk Drives Fulvestrant Resistance and Represents a Novel Therapeutic Target. bioRxiv : the preprint server for biology 1 41040402
2025 ACSS2 promotes proliferation and invasiveness of SKOV-3 and PA-1 ovarian cancer cell lines under hypoxia. Journal of ovarian research 1 41174639
2025 circRNA-02213 Regulates Milk Fat Synthesis in Bovine Mammary Epithelial Cells via ACSS2. Genes 1 41300803
2024 Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production. bioRxiv : the preprint server for biology 1 39026889
2024 ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells. bioRxiv : the preprint server for biology 1 39484430
2026 Crotonate suppresses breast cancer metastasis and promotes immunotherapy response by inducing ACSS2-mediated EZH2-K348 crotonylation. Science advances 0 41544165
2026 ACSS2 maintains oligodendrocyte progenitor cell pool and is required for myelination during development and aging. Nature aging 0 41781676
2026 Targeting ACSS2 disrupts metabolic-epigenetic crosstalk to restore apoptosis and temozolomide chemosensitivity in pancreatic neuroendocrine tumors. Cancer letters 0 41786280
2025 ACSS2 in pan-cancer context: multi-omics insights into metabolic reprogramming and immunotherapy response. Computers in biology and medicine 0 40729863
2025 ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function. FEBS letters 0 40936396

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