Affinage

ACSS2

Acetyl-coenzyme A synthetase, cytoplasmic · UniProt Q9NR19

Length
701 aa
Mass
78.6 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACSS2 is a nucleocytosolic acetyl-CoA synthetase that converts acetate to acetyl-CoA (and lactate to lactyl-CoA) to fuel both metabolic and epigenetic programs across diverse cell types. In the cytosol, ACSS2-generated acetyl-CoA supports de novo lipogenesis, fatty acid synthesis, and TCA cycle anaplerosis, serving as an essential alternative to ACLY-derived acetyl-CoA when citrate-dependent pathways are compromised (PMID:15, PMID:30228117, PMID:28407230). Signal-dependent phosphorylation—AMPK at S659 under glucose deprivation or ERK/CDK5 at S267 downstream of EGFR or OGT signaling—drives nuclear translocation, where ACSS2 associates with transcription factors (TFEB, PPARγ, SP1) and acetyltransferases (CBP, KAT2A, PCAF) to locally regenerate acetyl-CoA from deacetylation-released acetate, thereby sustaining targeted histone acetylation, crotonylation, and lactylation at promoters governing autophagy, lysosomal biogenesis, lipogenesis, immune evasion, and stress responses (PMID:28552616, PMID:39561764, PMID:35190642, PMID:38429478, PMID:37183518). ACSS2 also directly acetylates non-histone substrates—SP1 (K19) to stabilize it and PAICS to promote its autophagic degradation—thereby extending its regulatory reach beyond chromatin to transcription factor stability and purine metabolism (PMID:38429478, PMID:40021646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2015 Medium

    Establishing that ACSS2 links nutrient stress to transcription factor acetylation: it was unknown how acetyl-CoA was supplied for CBP-mediated HIF-2α acetylation under hypoxia/glucose deprivation; experiments showed ACSS2 is required to convert stress-elevated acetate into acetyl-CoA for CBP/HIF-2α complex formation, connecting metabolic stress sensing to HIF-2 transcriptional activation.

    Evidence ACSS2 knockdown/overexpression with HIF-2α acetylation assays, Co-IP, and mouse tumor models

    PMID:25689462

    Open questions at the time
    • Single lab; no ChIP to demonstrate chromatin-level mechanism
    • Direct ACSS2-CBP physical interaction not resolved at this stage
    • Whether ACSS2 nuclear entry is regulated was not addressed
  2. 2017 High

    Defining the AMPK–ACSS2 nuclear translocation axis and chromatin-level recycling mechanism: it was unknown how ACSS2 entered the nucleus or how acetyl-CoA was locally supplied at gene promoters; this work showed AMPK phosphorylates ACSS2 at S659, exposing an NLS for importin-α5 binding, and that nuclear ACSS2 binds TFEB at autophagy/lysosomal gene promoters to recapture histone deacetylation-derived acetate for local acetyl-CoA regeneration and histone H3 acetylation.

    Evidence AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2–importin-α5, ACSS2–TFEB), ChIP, nuclear fractionation, knock-in mutants, tumor growth assays

    PMID:28552616 PMID:28820290

    Open questions at the time
    • Whether other kinases also regulate ACSS2 nuclear entry was unresolved
    • Structural basis of acetate recycling at chromatin not determined
    • Generality beyond lysosomal/autophagy genes unknown
  3. 2017 Medium

    Identifying transcriptional regulation of ACSS2 by SREBP-1 and its role in de novo lipogenesis: it was unclear how ACSS2 expression itself was controlled; SREBP-1 was shown to directly bind the ACSS2 promoter SRE, and combined ACSS2/ACLY depletion abolished fatty acid and TAG synthesis.

    Evidence Luciferase reporter, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, lipid measurements

    PMID:28407230

    Open questions at the time
    • Only tested in mammary epithelial cells
    • Post-translational regulation of ACSS2 protein levels not addressed
  4. 2018 Medium

    Extending ACSS2's chromatin role to non-acetyl acyl modifications and viral latency: it was unknown whether ACSS2 could drive histone crotonylation; ACSS2 was shown to generate crotonyl-CoA that promotes histone crotonylation at the HIV LTR, reactivating latent provirus.

    Evidence siRNA knockdown, pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assays, SIV primate model

    PMID:29457784

    Open questions at the time
    • Direct in vitro crotonyl-CoA synthetase activity of purified ACSS2 was not reconstituted
    • Whether acetate or crotonate is the physiological substrate for crotonylation was unclear
  5. 2018 High

    Demonstrating ACSS2's whole-organism role in lipid metabolism: it was unknown whether ACSS2 loss would affect systemic lipid handling; ACSS2 knockout mice showed reduced intestinal lipid absorption and altered triglyceride repartitioning between adipose and liver in a fed/fasted state-dependent manner.

    Evidence ACSS2 knockout mice, diet-induced obesity model, gene expression profiling

    PMID:30228117

    Open questions at the time
    • Nuclear versus cytosolic contribution to the metabolic phenotype not dissected
    • Compensatory changes in ACLY or other acetyl-CoA sources not fully characterized
  6. 2022 High

    Revealing CDK5-mediated post-translational stabilization of ACSS2: it was unclear how ACSS2 protein levels were regulated; OGT-dependent CDK5 phosphorylation of ACSS2 at S267 was shown to reduce polyubiquitination and degradation, stabilizing ACSS2 and increasing acetyl-CoA and lipid production in glioblastoma.

    Evidence Phospho-site mutagenesis (S267), ubiquitination assays, metabolic tracing, in vivo GBM growth

    PMID:35190642

    Open questions at the time
    • Whether S267 phosphorylation also affects nuclear translocation (as later shown for ERK) was not tested
    • Identity of the E3 ligase mediating ACSS2 ubiquitination was not determined
  7. 2023 Medium

    Demonstrating ACSS2's nuclear role in alcohol-induced hepatic lipogenesis: it was unknown how ethanol-derived acetate reprograms lipogenic chromatin; nuclear ACSS2 was shown to recruit PCAF acetyltransferase for H3K9 acetylation at Fasn and Acaca promoters, driving hepatic steatosis.

    Evidence Liver-specific ACSS2 knockdown mice, CUT&RUN, Co-IP (PCAF–H3K9), ethanol feeding model

    PMID:37183518

    Open questions at the time
    • Whether ACSS2 directly binds PCAF or acts via intermediate complex not resolved
    • Contribution relative to ACLY in this context not quantified
  8. 2023 Medium

    Extending ACSS2's chromatin function to neuronal gene regulation: it was unknown whether ACSS2-dependent histone acetylation controlled synaptic receptor expression; hippocampal ACSS2 overexpression restored H3K9ac and H4K12ac at NMDAR/AMPAR promoters, rescuing synaptic plasticity and cognition in Alzheimer's disease mice.

    Evidence AAV-mediated ACSS2 overexpression, ChIP-qPCR, electrophysiology, Morris water maze

    PMID:37438762

    Open questions at the time
    • Overexpression-based; loss-of-function confirmation in neurodegeneration models lacking
    • Whether acetate availability is limiting in AD brain not established
  9. 2024 High

    Discovering ACSS2 as a lactyl-CoA synthetase and defining the EGFR–ERK–ACSS2–KAT2A histone lactylation axis: it was unknown how histone lactylation substrates were generated; ACSS2 was shown to convert lactate to lactyl-CoA downstream of ERK-mediated S267 phosphorylation, and a co-crystal structure revealed lactyl-CoA binding to KAT2A, which then lactylates histone H3 to drive PD-L1 and Wnt/NF-κB expression.

    Evidence In vitro lactyl-CoA synthetase assay, co-crystal structure (KAT2A–lactyl-CoA), ERK phosphorylation assay, Co-IP, ChIP, in vivo anti-PD-1 combination

    PMID:39561764

    Open questions at the time
    • Contradicts the 2024 finding that purified ACSS2 cannot use butyrate/crotonate—substrate specificity boundaries for short-chain acids need reconciliation
    • Whether lactyl-CoA synthesis is kinetically relevant at physiological lactate concentrations in vivo is unresolved
  10. 2024 High

    Clarifying ACSS2 substrate specificity: it was debated whether ACSS2 could generate crotonyl-CoA or butyryl-CoA; purified recombinant ACSS2 was shown to be unable to use butyrate or crotonate as substrates, restricting its primary activity to acetate-to-acetyl-CoA conversion.

    Evidence In vitro enzymatic assay with purified recombinant ACSS2, structural analysis

    PMID:38369012

    Open questions at the time
    • Does not address the lactyl-CoA synthetase activity reported separately
    • Cell-based crotonylation attributed to ACSS2 in prior studies remains mechanistically unexplained
  11. 2024 High

    Demonstrating ACSS2-mediated non-histone substrate acetylation: it was unknown whether ACSS2 directly acetylated non-histone proteins; ACSS2 was shown to acetylate SP1 at K19 (stabilizing SP1 for SAT1-driven polyamine reprogramming) and PAICS (promoting its autophagic degradation to limit purine biosynthesis and dNTP pools, exacerbating senescence-associated phenotypes).

    Evidence Co-IP, acetylation mass spectrometry, autophagy flux assays, dNTP measurements, ACSS2 KO mice, SASP profiling; ChIP-seq/RNA-seq for SP1/SAT1 axis in pancreatic cancer models

    PMID:38429478 PMID:40021646

    Open questions at the time
    • Whether ACSS2 itself has intrinsic acetyltransferase activity or channels acetyl-CoA to an acetyltransferase for these substrates is not fully distinguished
    • Range of non-histone substrates likely incomplete
  12. 2024 High

    Establishing ACSS2 as a compensatory acetyl-CoA source maintaining T cell effector chromatin: it was unknown whether ACSS2 could sustain epigenetic and metabolic programs when the primary ACLY pathway was absent; double-KO epistasis with 13C-acetate tracing showed ACSS2 maintains TCA fueling, histone acetylation, and chromatin accessibility at effector gene loci in CD8 T cells.

    Evidence ACLY KO, ACSS2 KO, double KO, 13C-acetate tracing, ATAC-seq, in vivo infection models

    PMID:39150482

    Open questions at the time
    • Relative contribution of ACSS2 versus ACLY under normal (non-KO) physiological conditions not quantified
    • Whether this compensation operates in other immune cell types untested
  13. 2024 High

    Linking ACSS2-driven lipogenesis to NLRP3 pyroptosis and kidney fibrosis: it was unknown how acetate metabolism caused tubular injury; ACSS2-produced acetyl-CoA was shown to drive de novo lipogenesis that depletes NADPH and elevates ROS, activating NLRP3-dependent pyroptosis; separately, ACSS2-produced crotonyl-CoA drives H3K9 crotonylation at the IL-1β locus, amplifying inflammation.

    Evidence ACSS2 KO mice, primary tubular cells, NADPH/ROS measurements, NLRP3 pathway, ChIP-seq/RNA-seq for H3K9cr, multiple fibrosis models

    PMID:38051585 PMID:38615014

    Open questions at the time
    • How ACSS2 generates crotonyl-CoA given its inability to use crotonate in vitro is mechanistically unexplained
    • Relative importance of lipogenesis-ROS versus H3K9cr-IL-1β arms not resolved
  14. 2024 Medium

    Defining ACSS2 as a PPARγ co-activator coupling activation to degradation in adipose plasticity: it was unknown how PPARγ activity was homeostatically regulated; ACSS2 was shown to bind acetylated PPARγ, recruit SIRT1 and PRDM16 for UCP1 activation, then facilitate PPARγ polyubiquitination and degradation via P300.

    Evidence Co-IP (ACSS2–PPARγ, ACSS2–SIRT1, ACSS2–PRDM16), ubiquitination assays, ACSS2 KO mice, high-fat diet model

    PMID:38332049

    Open questions at the time
    • Sequential model (activation then degradation) not validated by real-time dynamics
    • Structural basis of ACSS2–PPARγ interaction not determined
  15. 2025 Medium

    Connecting ACSS2–CBP to iron homeostasis regulation: it was unknown how acetyl-CoA metabolism influenced hepcidin transcription; ACSS2 was shown to bind CBP and maintain histone acetylation at HAMP1/2 promoters, with ACSS2 deficiency causing hepcidin downregulation, systemic iron dyshomeostasis, and hepatocyte ferroptosis in alcoholic liver disease.

    Evidence ACSS2 KO/overexpression, Co-IP (ACSS2–CBP), histone acetylation at HAMP promoters, iron metabolism and ferroptosis assays, rescue experiments

    PMID:40593779

    Open questions at the time
    • Whether the iron phenotype is direct or secondary to broader chromatin accessibility changes not resolved
    • Single lab, not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how ACSS2 generates crotonyl-CoA and lactyl-CoA in cells given its in vitro restriction to acetate; (2) whether ACSS2 possesses intrinsic protein acetyltransferase activity or solely channels acetyl-CoA to partner acetyltransferases; (3) the structural basis of ACSS2's association with diverse transcription factor and acetyltransferase partners; and (4) the relative quantitative contributions of ACSS2 versus ACLY to chromatin acetylation under physiological (non-KO) conditions in different tissues.
  • No high-resolution structure of full-length ACSS2 in complex with nuclear partners
  • No kinetic comparison of ACSS2 lactyl-CoA vs acetyl-CoA synthetase activity under physiological substrate concentrations
  • Tissue-specific isoform functions (ACSS2-S1 vs ACSS2-S2) remain poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0042393 histone binding 5 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 7 GO:0005829 cytosol 4
Pathway
R-HSA-4839726 Chromatin organization 8 R-HSA-1430728 Metabolism 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 2
Partners
CBPKAT2APAICSPCAFPPARΓSIRT1SP1TFEB

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, which exposes its nuclear localization signal for importin α5 (KPNA1) binding and nuclear translocation. In the nucleus, ACSS2 binds transcription factor EB (TFEB) and localizes to lysosomal and autophagy gene promoters, where it recaptures acetate from histone deacetylation to locally produce acetyl-CoA for histone H3 acetylation, promoting lysosomal biogenesis and autophagy. AMPK kinase assay, phospho-site mutagenesis, Co-IP (ACSS2-importin α5, ACSS2-TFEB), ChIP, nuclear fractionation, knock-in of nuclear translocation-deficient mutants, cell survival and tumor growth assays Molecular cell High 28552616 28820290
2024 EGFR activation induces ERK-mediated phosphorylation of ACSS2 at S267, promoting its nuclear translocation and complex formation with KAT2A. ACSS2 functions as a lactyl-CoA synthetase, converting lactate to lactyl-CoA; a co-crystal structure shows lactyl-CoA binding to KAT2A, which then acts as a lactyltransferase to lactylate histone H3, driving expression of Wnt/β-catenin, NF-κB, and PD-L1. In vitro lactyl-CoA synthetase assay, co-crystal structure of KAT2A with lactyl-CoA, ERK phosphorylation assay, Co-IP (ACSS2-KAT2A), ChIP, interaction-blocking peptide, anti-PD-1 combination treatment in vivo Cell metabolism High 39561764
2015 ACSS2 is required for CBP-mediated acetylation of HIF-2α during hypoxia and glucose deprivation; acetate levels rise during stress and ACSS2 supplies the acetyl-CoA needed for CBP/HIF-2α complex formation and HIF-2 transcriptional activation, linking nutrient sensing to stress signaling and tumor metastasis. ACSS2 knockdown/overexpression, acetate supplementation, HIF-2α acetylation assay, Co-IP (CBP/HIF-2α), colony formation/migration/invasion assays, mouse flank tumor model PloS one Medium 25689462
2017 ACSS2 promotes nuclear translocation in response to acetate/hypoxia/glucose deprivation, where it promotes acetylation of HIF-2α by CBP and regulates local histone 3 epigenetic marks; exogenous acetate augments ACSS2/HIF-2-dependent cancer growth and metastasis. Nuclear fractionation, acetate treatment, HIF-2α acetylation assay, Co-IP, mouse tumor model PloS one Medium 29281714
2018 ACSS2 expression generates crotonyl-CoA, which promotes histone crotonylation at the HIV LTR; ACSS2 induction reactivates latent HIV by reprogramming local chromatin through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminishes histone crotonylation-induced HIV reactivation. siRNA knockdown, ACSS2 pharmacologic inhibition, histone crotonylation ChIP, HIV reactivation assay (luciferase/viral outgrowth), SIV non-human primate model The Journal of clinical investigation Medium 29457784
2018 ACSS2 deficiency in mice reduces dietary lipid absorption by the intestine and perturbs repartitioning of triglycerides from adipose to liver by lowering expression of lipid transporters and fatty acid oxidation genes, demonstrating that ACSS2 selectively regulates genes involved in lipid metabolism according to fed/fasted state. ACSS2 knockout mice, diet-induced obesity model, body weight/hepatic steatosis measurements, gene expression analysis of lipid metabolism genes Proceedings of the National Academy of Sciences of the United States of America High 30228117
2022 OGT regulates acetate-dependent acetyl-CoA and lipid production in glioblastoma by controlling CDK5-dependent phosphorylation of ACSS2 at Ser-267, which reduces ACSS2 polyubiquitination and degradation, thereby stabilizing ACSS2 protein and increasing acetate-to-acetyl-CoA conversion. OGT overexpression/knockdown, CDK5 inhibition, phospho-site mutagenesis (Ser-267), ubiquitination assays, acetyl-CoA/lipid metabolic tracing, in vitro and in vivo GBM growth assays Oncogene High 35190642
2021 A transition-state mimetic small-molecule inhibitor of ACSS2 blocks its enzymatic activity (acetate-to-acetyl-CoA conversion) in vitro and in vivo, and pharmacologic inhibition as a single agent impairs breast tumor growth. In vitro ACSS2 enzymatic inhibition assay, transition-state mimetic synthesis, cell-based acetyl-CoA measurement, mouse breast tumor model Cancer research High 33414169
2024 ACSS2 channels exogenous CAF-derived acetate to regulate the cancer epigenome; it mediates acetylation of SP1 at lysine 19, increasing SP1 protein stability and transcriptional activity, which drives SAT1 expression and alters polyamine homeostasis to promote pancreatic cancer survival in an acidic microenvironment. H3K27ac ChIP-seq, RNA-seq, Co-IP, mass spectrometry (SP1-K19ac identification), ACSS2 genetic/pharmacologic inhibition, mouse tumor models Nature cell biology High 38429478
2024 ACSS2 regulates de novo lipogenesis (DNL) in kidney tubular cells by producing acetyl-CoA from acetate, causing NADPH depletion and ROS elevation that activates NLRP3-dependent pyroptosis; ACSS2-KO mice are protected from kidney fibrosis in multiple disease models. ACSS2 knockout mice, primary tubular cell cultures, NADPH/ROS measurements, NLRP3 pathway analysis, fatty acid synthase inhibition, multiple fibrosis models The Journal of clinical investigation High 38051585
2024 ACSS2-produced crotonyl-CoA drives H3K9 crotonylation (H3K9cr) in tubular epithelial cells, and H3K9cr at the IL-1β locus upregulates IL-1β expression, promoting macrophage activation and tubular cell senescence in kidney fibrosis; genetic and pharmacologic ACSS2 inhibition suppresses H3K9cr-mediated IL-1β and delays renal fibrosis. ChIP-seq, RNA-seq, ACSS2 genetic knockdown and pharmacologic inhibition, H3K9cr/H3K9ac measurements, IL-1β expression, macrophage co-culture, fibrosis models Nature communications High 38615014
2024 ACSS2 directly interacts with and acetylates PAICS (a key purine biosynthesis enzyme) using locally produced acetyl-CoA; PAICS acetylation promotes its autophagy-mediated degradation, limiting purine metabolism and dNTP pools for DNA repair, thereby exacerbating cytoplasmic chromatin fragment accumulation and the senescence-associated secretory phenotype (SASP). Co-IP (ACSS2-PAICS), acetylation mass spectrometry, autophagy flux assays, dNTP pool measurements, Acss2 knockout mice, SASP cytokine profiling Nature communications High 40021646
2024 ACSS2 controls PPARγ activity homeostasis by binding directly to acetylated PPARγ in the presence of ligand and recruiting SIRT1 and PRDM16 to activate UCP1 expression; SIRT1 then deacetylates PPARγ and triggers ACSS2 translocation to P300, inducing PPARγ polyubiquitination and degradation, thereby coupling PPARγ activation with degradation to enhance adipose plasticity. Co-IP (ACSS2-PPARγ, ACSS2-SIRT1, ACSS2-PRDM16), acetylation/ubiquitination assays, ACSS2 KO mice, UCP1 reporter, high-fat diet model with D-mannose treatment Cell death and differentiation Medium 38332049
2024 ACSS2 inhibition reduces chromatin accessibility and HIF-2α expression and stability in clear cell renal cell carcinoma; mechanistically, loss of ACSS2 promotes HIF-2α degradation via a pVHL-independent pathway involving the E3 ligase MUL1, which directly interacts with HIF-2α. ACSS2 inhibition, ATAC-seq (chromatin accessibility), HIF-2α protein stability assays, Co-IP (MUL1-HIF-2α), MUL1 overexpression, primary patient tumor cultures, in vivo ccRCC models The Journal of clinical investigation Medium 38941296
2024 ACSS2 is unable to generate butyryl-CoA or crotonyl-CoA from butyrate or crotonate in direct in vitro enzymatic assays with purified/recombinant enzyme, demonstrating its substrate specificity is restricted to acetate for acetyl-CoA production. In vitro enzymatic assay with purified recombinant ACSS2, structural analysis Molecular metabolism High 38369012
2024 In CD8 T cells, when ACLY (the primary cytosolic acetyl-CoA source from citrate) is ablated, ACSS2 mediates an alternative acetate-dependent pathway for acetyl-CoA production that maintains TCA cycle fueling, histone acetylation, and chromatin accessibility at effector gene loci to sustain T cell effector function in vivo. ACLY KO, ACSS2 KO (single and double), stable isotope (13C-acetate) tracing, ATAC-seq, histone acetylation assays, in vivo infection models The Journal of experimental medicine High 39150482
2023 ACSS2 upregulation in Alzheimer's disease mouse hippocampus restores H3K9ac and H4K12ac enrichment at NMDAR and AMPAR gene promoters, increasing receptor expression and rescuing synaptic plasticity and cognitive function; acetate replenishment achieves the same effect in an ACSS2-dependent manner. AAV-mediated ACSS2 overexpression in dorsal hippocampus, ChIP-qPCR (H3K9ac, H4K12ac at NMDAR/AMPAR promoters), RNA-seq, electrophysiology (LTP), Morris water maze Molecular neurodegeneration Medium 37438762
2023 ACSS2 mediates NF-κB-dependent downregulation of CA9 in pancreatic cancer cells during alkaliptosis by producing acetyl-CoA that supports histone acetylation; this contributes to intracellular pH decrease and pH-dependent cell death. ACSS2 shRNA knockdown, western blot/qPCR, intracellular pH measurement, histone acetylation assay, HDAC inhibitor (TSA) combined treatment Scientific reports Low 36707625
2023 Alcohol metabolism generates acetate that promotes ACSS2 nuclear import; nuclear ACSS2 recruits PCAF acetyltransferase to mediate H3K9 acetylation at Fasn and Acaca promoters, driving lipogenic gene expression and hepatic steatosis. Liver-specific ACSS2 knockdown mice, CUT&RUN (H3K9ac at Fasn/Acaca promoters), Co-IP (PCAF-H3K9), nuclear fractionation, ethanol feeding model Liver international Medium 37183518
2025 ACSS2 binds CBP to mediate histone acetylation and regulate hepcidin (HAMP1/2) transcription; ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and hepatocyte ferroptosis in alcoholic liver disease. ACSS2 KO/overexpression, Co-IP (ACSS2-CBP), histone acetylation at HAMP1/2 promoters, iron metabolism measurements, ferroptosis assays, HAMP1/2 rescue overexpression Nature communications Medium 40593779
2020 NRF2 transcriptionally upregulates ACSS2 in esophageal squamous cell carcinoma cells; ACSS2 converts ethanol-derived acetate to acetyl-CoA, increasing ATP levels and driving lipid synthesis and invasive capability in NRF2-high cells exposed to ethanol. NRF2/ACSS2 siRNA knockdown, acetyl-CoA/ATP metabolic measurements, lipid synthesis assays, invasion assays, ethanol exposure The Biochemical journal Medium 32776152
2017 SREBP-1 directly regulates ACSS2 transcription by binding an SRE element at −475 to −483 bp on the ACSS2 promoter as demonstrated by luciferase reporter and ChIP assay; simultaneous knockdown of ACSS2 and ACLY reduces de novo fatty acid synthesis, TAG synthesis, and lipid droplet formation in mammary epithelial cells. Luciferase reporter assay, ChIP (SREBP-1 at ACSS2 promoter), siRNA double knockdown, TAG content measurement, lipid droplet staining Journal of cellular physiology Medium 28407230
2019 Alternative transcription start site selection in ACSS2 generates two isoforms (ACSS2-S1 and ACSS2-S2) with different subcellular localizations: ACSS2-S1 is cytoplasmic, while ACSS2-S2 distributes in both nucleus and cytoplasm. ACSS2-S2 overexpression promotes cell proliferation, invasion, and ribosome biogenesis in hepatocellular carcinoma, whereas ACSS2-S1 does not. Transcription start site sequencing, subcellular fractionation/immunofluorescence, isoform-specific overexpression, proliferation/invasion assays, ribosome biogenesis analysis Biochemical and biophysical research communications Low 31076106
2024 ACSS2 interacts with HMGCS1 (by Co-IP) to regulate lipid metabolism reprogramming and the PI3K/AKT/mTOR pathway in pancreatic neuroendocrine neoplasms; HMGCS1 overexpression reverses the lipogenic and pro-tumorigenic effects of ACSS2 knockdown. Co-IP (ACSS2-HMGCS1), CCK-8/colony formation/EdU proliferation assays, transwell invasion, nude mouse xenografts, PI3K/AKT/mTOR pathway analysis Journal of translational medicine Low 38263056
2024 SCAP N-glycosylation increases both SREBP-1-mediated ACSS2 transcription and AMPK-mediated S659 phosphorylation of ACSS2, promoting nuclear ACSS2 accumulation and H3K27 acetylation, which drives lipogenic gene expression and hepatic inflammation in NASH. SCAP N-glycosylation site mutagenesis, ACSS2 expression/localization assays, AMPK phosphorylation assay, H3K27ac measurements, lipid accumulation assays in hepatic cell lines American journal of physiology. Gastrointestinal and liver physiology Medium 38591127
2024 ACSS2 promotes neuronal TPH2 transcription by binding PPARγ as a co-activator and supporting histone acetylation at the TPH2 promoter; ACSS2 is required for SCFA-mediated antidepressant responses, and PPARγ is identified as a novel ACSS2 partner for activating CRTC1 transcription. Stereotaxic AAV-mediated neuronal ACSS2 knockdown, Co-IP/interaction assay (ACSS2-PPARγ), ChIP (histone acetylation at TPH2/CRTC1 promoters), behavioral tests (chronic-restraint-stress model) Research (Washington, D.C.) Medium 38939042

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 287 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 168 39561764
2005 Eto Brute? Role of ACS turnover in regulating ethylene biosynthesis. Trends in plant science 143 15949763
2008 Regulation of ACS protein stability by cytokinin and brassinosteroid. The Plant journal : for cell and molecular biology 139 18980656
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 130 30228117
2018 HIV latency is reversed by ACSS2-driven histone crotonylation. The Journal of clinical investigation 128 29457784
2006 Control of acetyl-coenzyme A synthetase (AcsA) activity by acetylation/deacetylation without NAD(+) involvement in Bacillus subtilis. Journal of bacteriology 122 16855235
2003 The gene yjcG, cotranscribed with the gene acs, encodes an acetate permease in Escherichia coli. Journal of bacteriology 103 14563880
2015 The response of guinea pig primary utricular and saccular irregular neurons to bone-conducted vibration (BCV) and air-conducted sound (ACS). Hearing research 101 26626360
2020 Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study. European heart journal 92 33080003
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 91 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 88 28407230
2024 Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence. Nature communications 78 38615014
2021 Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth. Cancer research 78 33414169
2017 Anti-ACSA-2 defines a novel monoclonal antibody for prospective isolation of living neonatal and adult astrocytes. Glia 78 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
2017 Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy 68 28820290
2024 Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. Nature cell biology 66 38429478
2010 Two very long chain fatty acid acyl-CoA synthetase genes, acs-20 and acs-22, have roles in the cuticle surface barrier in Caenorhabditis elegans. PloS one 64 20111596
2019 Acute and 1-Year Hospitalization Costs for Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention: Results From the TRANSLATE-ACS Registry. Journal of the American Heart Association 62 30975005
2015 The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PloS one 62 25689462
2023 ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease. Molecular neurodegeneration 61 37438762
2022 Acetyl-CoA synthetase 2(ACSS2): a review with a focus on metabolism and tumor development. Discover oncology 55 35798917
1999 Clinical evaluation of rhBMP-2/ACS in orthopedic trauma: a progress report. Orthopedics 53 10418860
2024 Sodium butyrate alleviates lead-induced neuroinflammation and improves cognitive and memory impairment through the ACSS2/H3K9ac/BDNF pathway. Environment international 51 38340407
2022 O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation. Oncogene 50 35190642
2014 Factors predicting future ACS episodes in children with sickle cell anemia. American journal of hematology 48 25088663
2006 Sirtuins: a conserved key unlocking AceCS activity. Trends in biochemical sciences 47 17141505
1998 Expression of the Bacillus subtilis acsA gene: position and sequence context affect cre-mediated carbon catabolite repression. Journal of bacteriology 45 9852010
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 44 18487328
1997 Clinical and technical evaluation of ACS BR serum assay of MUC1 gene-derived glycoprotein in breast cancer, and comparison with CA 15-3 assays. Clinical chemistry 44 9105258
2021 Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy. Environmental pollution (Barking, Essex : 1987) 42 33486244
2020 Optimal Timing of Intervention in NSTE-ACS Without Pre-Treatment: The EARLY Randomized Trial. JACC. Cardiovascular interventions 41 32327087
2021 Sex and gender differences in presentation, treatment and outcomes in acute coronary syndrome, a 10 year study from a multi-ethnic Asian population: The Malaysian National Cardiovascular Disease Database-Acute Coronary Syndrome (NCVD-ACS) registry. PloS one 38 33556136
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 37 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 37 29883801
2015 Association of Discharge Aspirin Dose With Outcomes After Acute Myocardial Infarction: Insights From the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. Circulation 37 25995313
2023 Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO-ACS study. European heart journal 36 37381760
2021 Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer-Results from Phase Ib Trial IMU.ACS.001. Clinical cancer research : an official journal of the American Association for Cancer Research 35 33879458
2023 P2Y12 Inhibitor Monotherapy Combined With Colchicine Following PCI in ACS Patients: The MACT Pilot Study. JACC. Cardiovascular interventions 34 37587591
2023 ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules. The Journal of clinical investigation 34 38051585
2017 Fatty Acids Regulate Germline Sex Determination through ACS-4-Dependent Myristoylation. Cell 33 28431246
2017 Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells. PloS one 33 29281714
2023 ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells. Scientific reports 31 36707625
2010 Cost-effectiveness of adenotonsillectomy in reducing obstructive sleep apnea, cerebrovascular ischemia, vaso-occlusive pain, and ACS episodes in pediatric sickle cell disease. Annals of hematology 31 20714723
2014 Defects in the C. elegans acyl-CoA synthase, acs-3, and nuclear hormone receptor, nhr-25, cause sensitivity to distinct, but overlapping stresses. PloS one 30 24651852
2005 Acetate excretion during growth of Salmonella enterica on ethanolamine requires phosphotransacetylase (EutD) activity, and acetate recapture requires acetyl-CoA synthetase (Acs) and phosphotransacetylase (Pta) activities. Microbiology (Reading, England) 30 16272400
2020 Lipid-lowering therapy and low-density lipoprotein cholesterol goal achievement in patients with acute coronary syndromes: The ACS patient pathway project. Atherosclerosis. Supplements 29 33589224
2019 The importance of return to work: How to achieve optimal reintegration in ACS patients. European journal of preventive cardiology 29 30971111
2000 Cellular localization of type 5 and type 6 ACs in collecting duct and regulation of cAMP synthesis. American journal of physiology. Renal physiology 29 10894801
2001 The Pseudomonas aeruginosa acsA gene, encoding an acetyl-CoA synthetase, is essential for growth on ethanol. Microbiology (Reading, England) 26 11577146
2023 Extracellular vesicles derived from human ESC-MSCs target macrophage and promote anti-inflammation process, angiogenesis, and functional recovery in ACS-induced severe skeletal muscle injury. Stem cell research & therapy 25 37964317
2022 Acetyl-CoA synthetases ACSS1 and ACSS2 are 4-hydroxytamoxifen responsive factors that promote survival in tamoxifen treated and estrogen deprived cells. Translational oncology 23 35263700
2024 ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. The Journal of experimental medicine 22 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 22 39362518
2016 A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome: The design of the GEMINI-ACS-1 phase II study. American heart journal 22 26995378
2015 Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions? Thrombosis and haemostasis 21 26085050
2023 Targeted Alpha Therapy: All We Need to Know about 225Ac's Physical Characteristics and Production as a Potential Theranostic Radionuclide. Pharmaceuticals (Basel, Switzerland) 20 38139806
2021 Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art. Journal of clinical medicine 20 33916362
2007 Measurement and clinical significance of circulating PAPP-A in ACS patients. Clinica chimica acta; international journal of clinical chemistry 20 17376420
2024 ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity. Cell death and differentiation 19 38332049
2010 Transcriptional regulation of the acetyl-CoA synthetase gene acsA in Pseudomonas aeruginosa. Archives of microbiology 19 20549193
2024 Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells. Frontiers in pharmacology 18 38818373
2024 HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma. The Journal of clinical investigation 18 38941296
2016 Gamma-irradiation produces active chlorine species (ACS) in physiological solutions: Secoisolariciresinol diglucoside (SDG) scavenges ACS - A novel mechanism of DNA radioprotection. Biochimica et biophysica acta 18 27261092
2021 Rapamycin antagonizes cadmium-induced breast cancer cell proliferation and metastasis through directly modulating ACSS2. Ecotoxicology and environmental safety 16 34411822
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
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
2014 The "dual-pathway" strategy after acute coronary syndrome: rivaroxaban and antiplatelet agents in the ATLAS ACS 2-TIMI 51 trial. Cardiovascular therapeutics 14 24894120
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 13 37183518
2023 High-fat diet-induced gut microbiota alteration promotes lipogenesis by butyric acid/miR-204/ACSS2 axis in chickens. Poultry science 13 37390560
2019 ACSS2/AMPK/PCNA pathway‑driven proliferation and chemoresistance of esophageal squamous carcinoma cells under nutrient stress. Molecular medicine reports 13 31638228
2015 Potential Role of Acetyl-CoA Synthetase (acs) and Malate Dehydrogenase (mae) in the Evolution of the Acetate Switch in Bacteria and Archaea. Scientific reports 13 26235787
2021 Vascular damage effect of circulating microparticles in patients with ACS is aggravated by type 2 diabetes. Molecular medicine reports 12 33899122
2016 Factors Associated With Initial Prasugrel Versus Clopidogrel Selection for Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Insights From the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study. Journal of the American Heart Association 12 27663414
2012 Lost in follow-up rates in TRACER, ATLAS ACS 2, TRITON and TRA 2P trials: challenging PLATO mortality rates. International journal of cardiology 12 23068568
2025 ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation. Nature communications 11 40021646
2024 Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis. Research (Washington, D.C.) 11 38939042
2024 Paeoniflorin alleviates toxicity and accumulation of 6-PPD quinone by activating ACS-22 in Caenorhabditis elegans. Ecotoxicology and environmental safety 11 39442254
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
2001 Clinical evaluation of the ACS:180 cardiac troponin I assay. Annals of clinical biochemistry 11 11587129
2021 ACSA-2 and GLAST classify subpopulations of multipotent and glial-restricted cerebellar precursors. Journal of neuroscience research 10 34060113
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
2019 Relation of White Blood Cell Count to Bleeding and Ischemic Events in Patients With Acute Coronary Syndrome (from the ATLAS ACS 2-TIMI 51 Trial). The American journal of cardiology 10 31898965
2017 Addition of biomarker panel improves prediction performance of American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) calculator for cardiac risk assessment of elderly patients preparing for major non-cardiac surgery: a pilot study. Aging clinical and experimental research 10 28752477
2025 ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target. Lipids in health and disease 9 40001058
2025 Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacological research 9 40127788
2024 In-Hospital Mortality and Treatment in Patients With Acute Coronary Syndrome With and Without Standard Modifiable Cardiovascular Risk Factors: Findings From the CCC-ACS Project. Journal of the American Heart Association 9 39291502
2016 Case Study: Ticagrelor in PLATO and Prasugrel in TRITON-TIMI 38 and TRILOGY-ACS Trials in Patients With Acute Coronary Syndromes. American journal of therapeutics 9 25830867
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 N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation. American journal of physiology. Gastrointestinal and liver physiology 8 38591127
2019 ACSS2-related autophagy has a dual impact on memory. Chinese neurosurgical journal 8 32922914
2007 Embryonic expression patterns of Drosophila ACS family genes related to the human sialin gene. Gene expression patterns : GEP 8 18255354
2025 ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression. Nature communications 7 40593779
2019 Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation. Alcoholism, clinical and experimental research 7 31283017