Affinage

ACLY

ATP-citrate synthase · UniProt P53396

Length
1101 aa
Mass
120.8 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACLY is the central cytosolic enzyme that converts mitochondrially-derived citrate into acetyl-CoA, providing the carbon source that links central carbon metabolism to both de novo lipogenesis and acetyl-CoA-dependent histone/protein acetylation (PMID:39881208, PMID:39150482). A defining feature is its dual subcellular partitioning: AKT-mediated S455 phosphorylation drives nuclear translocation, where ACLY locally generates acetyl-CoA for histone acetyltransferases to write locus-specific marks, governing DNA double-strand-break repair pathway choice toward homologous recombination (PMID:28689661), cytokine-driven cell-cycle gene expression in T cells (PMID:27067055), osteoclast differentiation via GCN5-dependent H3 acetylation of Rac1 (PMID:34155695), and Foxa2-mediated protective programs during hepatic ischemia-reperfusion (PMID:37983829). In the cytosol, ACLY-derived acetyl-CoA fuels fatty acid and cholesterol synthesis, a function exploited therapeutically by CoA-thioester prodrug inhibitors that lower hepatic lipogenesis and atherosclerosis (PMID:31499095, PMID:36873173), with cryo-EM confirming inhibitor occupancy of the CoA-binding site (PMID:40739358). ACLY abundance and activity are tightly controlled post-translationally — by acetylation that is balanced against ubiquitin-proteasomal and selective-autophagic degradation through multiple E3 ligases and deacetylases (PMID:32888949, PMID:35404187, PMID:38426936, PMID:39881208) — and transcriptionally by stress- and metabolism-responsive factors (PMID:32589900, PMID:38009671). Through the SLC25A1–ACLY axis, ACLY-derived acetyl-CoA sustains FSP1 acetylation to suppress ferroptosis (PMID:39881208), and ACLY activity broadly couples metabolic state to chromatin accessibility at effector gene loci (PMID:39150482, PMID:33325591). ACLY also acts in disease contexts including alpha-synuclein-driven mTORC1 hyperactivation in Parkinson neurons (PMID:40262613) and innate-immune activation via cGAS-STING upon its inhibition (PMID:38055816).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 High

    Established that ACLY-dependent metabolic flux shapes cell fate under hypoxia, beyond simply supplying lipids, by controlling oncogenic transcription via metabolite levels.

    Evidence Genome-wide shRNA screen with metabolomics and α-ketoglutarate rescue in cancer cells

    PMID:26452058

    Open questions at the time
    • Mechanism by which α-ketoglutarate epigenetically suppresses ETV4 not resolved
    • Did not address nuclear vs cytosolic ACLY pools
  2. 2016 High

    Linked cytokine signaling to ACLY function by showing AKT-driven S455 phosphorylation enables ACLY to support histone acetylation and proliferation in T cells.

    Evidence Nuclear phosphoproteomics, knockdown, inhibitor, and proliferation assays in CD4+ T cells; AMPK-AR feedback loop in prostate cancer

    PMID:27067055 PMID:27248322

    Open questions at the time
    • Direct demonstration of nuclear acetyl-CoA generation not yet shown
    • Which HATs use ACLY-derived acetyl-CoA not defined
  3. 2017 High

    Resolved that ACLY operates directly at chromatin by showing ATM/AKT-driven nuclear ACLY supplies acetyl-CoA at DSB sites to bias repair toward homologous recombination.

    Evidence Phospho-site mutagenesis, nuclear fractionation, HR/NHEJ reporters, chromatin IF

    PMID:28689661

    Open questions at the time
    • HAT partner at DSB sites not identified
    • Quantitative contribution of local vs bulk acetyl-CoA unclear
  4. 2020 Medium

    Defined ACLY enzymatic regulation by lipid second messengers and tyrosine phosphorylation, and identified ERAD-mediated proteostatic control of its abundance.

    Evidence PIP-binding domain mapping and Lyn kinase assays in AML; Co-IP/MS identification of Hrd1 with in vivo functional rescue

    PMID:32420483 PMID:32888949

    Open questions at the time
    • PIP2/PIP3 binding effect on activity from single lab
    • Structural basis of tyrosine-phosphorylation-driven activation not resolved
  5. 2021 High

    Generalized nuclear ACLY's role across cell types, demonstrating GCN5/KAT2B as the cooperating HAT and identifying deacetylase control of nuclear ACLY pools.

    Evidence RANKL differentiation with ACLY-GCN5 epistasis and ChIP in osteoclasts; SIRT6 inactivation with nuclear ACLY quantification; STAT3 promoter binding in endometrial cancer

    PMID:33991616 PMID:34155695 PMID:34573442

    Open questions at the time
    • Mechanism of ACLY nuclear import not defined
    • How SIRT6 controls nuclear ACLY levels mechanistically unclear
  6. 2022 Medium

    Mapped a network of acetylation-dependent stability control, where acetylation protects ACLY from ubiquitin ligase recruitment and deacetylation destabilizes it, plus selective autophagic turnover.

    Evidence Acetylation-site mutagenesis with NEDD4 interaction (ARHGEF3); SIRT2 deacetylation rescue; K63-ubiquitin/SQSTM1 autophagy assays in granulosa cells

    PMID:35404187 PMID:36241648 PMID:38426936

    Open questions at the time
    • Cross-talk between acetylation, K48 and K63 ubiquitination on the same residues not integrated
    • Most interactions from single labs without reciprocal validation
  7. 2023 High

    Extended ACLY regulation to ER-stress and metabolic signaling inputs and reinforced the functional distinction between nuclear and cytosolic ACLY in tissue protection.

    Evidence Hepatocyte-specific ACLY KO with CUT&RUN (IR injury); SEC63/IRE1α stabilization assays; ENDOG-mTORC2-AKT axis; FBXW7 degradation; ACLY-BP micropeptide protection

    PMID:37122003 PMID:37409966 PMID:37794041 PMID:37983829 PMID:39781455

    Open questions at the time
    • Signals determining nuclear vs cytosolic partitioning in different tissues not unified
    • Several upstream regulators characterized in single contexts
  8. 2024 High

    Demonstrated ACLY couples metabolism to chromatin accessibility and immunity, revealed isoform- and lactylation-based activity control, and uncovered immunogenic consequences of ACLY inhibition.

    Evidence Conditional ACLY/ACSS2 KO with ATAC-seq/ChIP-seq in CD8 T cells; RBM25-controlled splice isoform with lactylation site mapping in macrophages; cGAS-STING activation upon ACLY inhibition; ChIP-linked fibrotic gene control in cardiac fibroblasts

    PMID:33325591 PMID:38055816 PMID:39150482 PMID:39251781 PMID:40047081

    Open questions at the time
    • Functional consequence of lactylation from single lab
    • Determinants of compensatory ACSS2 engagement across tissues not defined
  9. 2025 High

    Provided structural validation of inhibitor binding and connected the SLC25A1-ACLY axis to ferroptosis suppression and anti-tumor immunity, while linking ACLY to neurodegeneration.

    Evidence Cryo-EM of inhibitor-CoA bound ACLY with hepatocyte KO in MASH-HCC; CRISPR SLC screen with FSP1 acetylation/ubiquitination assays; multi-model alpha-synuclein PD rescue; biophysical on-target inhibitor validation in atherosclerosis

    PMID:39881208 PMID:40225566 PMID:40262613 PMID:40739358

    Open questions at the time
    • Whether nuclear ACLY contributes to FSP1 regulation unaddressed
    • Tissue-specificity of immune consequences across tumor types not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular signals and import machinery determining ACLY's cytosolic-versus-nuclear partitioning, and how the competing acetylation/ubiquitination/lactylation marks are coordinated on the same protein in vivo, remain unresolved.
  • No defined nuclear import mechanism for ACLY
  • No integrated model reconciling the multiple post-translational regulatory inputs
  • Structural basis for activity modulation by phosphorylation/acetylation lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0016829 lyase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-4839726 Chromatin organization 4 R-HSA-5357801 Programmed Cell Death 2
Partners
ARHGEF3CTNNB1FBXW7GCN5/KAT2BNEDD4SEC63SLC25A1SQSTM1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Nuclear ACLY is phosphorylated at S455 downstream of ATM and AKT following DNA double-strand breaks; this phosphorylation and nuclear localization enable ACLY to generate acetyl-CoA at DSB sites, promote histone acetylation, impair 53BP1 localization, and facilitate BRCA1 recruitment for homologous recombination repair. Phosphorylation-site mutagenesis, nuclear fractionation/localization experiments, siRNA knockdown with HR/NHEJ reporter assays, Co-IP, chromatin immunofluorescence Molecular cell High 28689661
2016 ACLY is phosphorylated on serine 455 in CD4+ T lymphocytes upon IL-2-driven AKT activation; this phosphorylation is required for ACLY to enhance histone acetylation levels and induce cell-cycle gene expression, linking cytokine signaling to T-cell proliferation. Mass spectrometry-based nuclear phosphoproteomics, siRNA knockdown, pharmacological ACLY inhibition, histone acetylation quantification, cell-cycle/proliferation assays Molecular & cellular proteomics : MCP High 27067055
2020 Hrd1, a subunit of the ER-associated degradation (ERAD) complex, interacts with ACLY and ubiquitinates it, promoting its proteasomal degradation and thereby reducing acetyl-CoA levels and lipogenesis in hepatocytes. Co-IP/mass spectrometry, co-immunoblotting, acetyl-CoA measurement, lipogenesis assays, adenovirus-mediated overexpression in db/db mice Metabolism: clinical and experimental High 32888949
2022 ACLY undergoes K63-linked ubiquitination and is selectively recognized by the autophagy receptor SQSTM1/p62 for autophagic degradation in granulosa cells; this selective autophagy maintains citrate homeostasis and supports oocyte maturation. Co-IP with ubiquitin-linkage-specific antibodies, autophagy flux assays, SQSTM1 pulldown, granulosa cell autophagy inhibition/ablation, metabolomics, oocyte maturation scoring Autophagy High 35404187
2021 RANKL-induced ACLY activation leads to nuclear translocation of ACLY in osteoclast precursors; nuclear ACLY supplies acetyl-CoA to GCN5 for H3 acetylation, and ACLY and GCN5 function in the same pathway to transcriptionally regulate Rac1 and thereby promote osteoclast differentiation and cytoskeletal organization. RANKL-stimulated differentiation assays, siRNA knockdown, ACLY inhibitor (BMS-303141), acetyl-CoA measurement, nuclear fractionation, ChIP, RNA-seq, GCN5 knockdown/overexpression epistasis, OVX mouse model Journal of bone and mineral research High 34155695
2020 PIP2 (the PI3K substrate) and PIP3 (the PI3K product) bind directly to the CoA-binding domain of ACLY in AML cells; the Src-family kinase Lyn phosphorylates ACLY at six tyrosine residues (including Y682, Y252, Y227 located in catalytic, citrate-binding, and ATP-binding domains), stimulating ACLY enzymatic activity, acetyl-CoA synthesis, phospholipid synthesis, and histone acetylation. PIP-binding assays (domain mapping), in vitro kinase assay with Lyn/Src, mass spectrometry phosphosite identification, PI3K/Lyn inhibitor treatment with enzymatic activity readouts Heliyon Medium 32420483
2019 ACLY physically interacts with and stabilizes CTNNB1 (β-catenin), promoting its translocation from cytoplasm to nucleus and enhancing CTNNB1 transcriptional activity to drive colon cancer cell migration and invasion. Co-IP, western blot, migration/invasion assays in ACLY-deficient cell lines, in vivo mouse colon metastasis model Journal of experimental & clinical cancer research : CR Medium 31511060
2015 Loss of ACLY (or ACC1) protects cancer cells from hypoxia-induced apoptosis by paradoxically elevating α-ketoglutarate levels under hypoxia, which suppresses the expression and activity of the oncogenic transcription factor ETV4 via an epigenetic mechanism; supplementation with α-ketoglutarate recapitulates both ETV4 suppression and apoptosis protection. Genome-wide shRNA screen, metabolomics, α-ketoglutarate supplementation rescue, ETV4 knockdown epistasis, transcriptional profiling PLoS genetics High 26452058
2016 ACLY-dependent fatty acid synthesis maintains AR protein levels in castration-resistant prostate cancer cells; ACLY inhibition combined with AR antagonism activates AMPK and further suppresses AR, and exogenous fatty acid supplementation restores AR levels and ER homeostasis, identifying an ACLY-AMPK-AR feedback loop. ACLY inhibitor treatment, AMPK activation measurement, AR protein/mRNA quantification, fatty acid rescue experiments, ER stress assays, gene expression correlation in human tumor data Oncotarget Medium 27248322
2021 Nuclear translocation of ACLY, driven by AKT-mediated S455 phosphorylation in response to obesity-related factors (estradiol, insulin, leptin), increases histone acetylation at pyrimidine metabolism gene promoters (including DHODH) in endometrial cancer cells; STAT3 regulates ACLY expression at the transcriptional level by directly binding its promoter. Nuclear fractionation, phospho-site analysis, ChIP, siRNA knockdown, AKT inhibitor, promoter-binding assays Cancer letters Medium 33991616
2023 SEC63 is phosphorylated at T537 by the IRE1α pathway upon ER stress; phosphorylated SEC63 stabilizes ACLY protein to increase acetyl-CoA and lipid biosynthesis; nuclear SEC63 coordinates with ACLY to epigenetically upregulate Snail1 expression, promoting HCC metastasis. GST pulldown, immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assays, immunofluorescence, RNA-seq, transwell assays Journal of experimental & clinical cancer research : CR Medium 37122003
2022 SIRT2 deacetylates ACLY protein; SIRT2 inhibition increases ACLY acetylation and inhibits ESCC cell proliferation and migration, while ACLY overexpression partially rescues the inhibitory effect, placing SIRT2-mediated deacetylation upstream of ACLY stability and activity. Co-IP, acetylation immunoblotting, SIRT2 inhibitor (AGK2) treatment, ACLY overexpression rescue, proliferation/migration assays Journal of cellular and molecular medicine Medium 38426936
2022 ARHGEF3 stabilizes ACLY protein by reducing its acetylation on Lys17 and Lys86, thereby preventing the binding of the E3 ligase NEDD4 to ACLY and its ubiquitin-mediated degradation; this function of ARHGEF3 is independent of its GEF activity. Co-IP, acetylation site mutagenesis (K17/K86), NEDD4 interaction assays, ARHGEF3 GEF-dead mutant, proliferation assays Cell death & disease Medium 36241648
2023 ACLY-BP, a micropeptide encoded by LINC00887, physically associates with ACLY and maintains its acetylation, preventing ACLY ubiquitylation and proteasomal degradation, thereby sustaining lipid deposition and cell proliferation in clear cell renal cell carcinoma. Co-IP, acetylation/ubiquitination assays, ACLY-BP knockdown/overexpression, lipid quantification, tumor growth assays Molecular cancer research : MCR Medium 37409966
2024 The RNA-binding protein RBM25 promotes exon 14 skipping of ACLY pre-mRNA, generating a short isoform (ACLY S) that lacks the lactylation sites (K918/K995) present in the long isoform (ACLY L); ACLY L is subject to protein lactylation which reduces its metabolic activity, whereas the ACLY S isoform enhances glycolysis and acetyl-CoA production for epigenetic remodeling and macrophage overactivation. RNA-seq splice isoform analysis, mass spectrometry-based lactylation site mapping, RBM25 knockdown, isoform-specific overexpression, metabolic flux assays, ChIP Cellular & molecular immunology Medium 39251781
2025 SLC25A1 exports citrate from mitochondria to the cytosol where ACLY converts it to acetyl-CoA; this acetyl-CoA sustains FSP1 acetylation (primarily at K168 by KAT2B, reversed by HDAC3), preventing K29-linked ubiquitin-mediated proteasomal degradation of FSP1 and thereby suppressing ferroptosis. CRISPR-Cas9 SLC superfamily screen, co-IP, in vitro acetylation/deacetylation assays (KAT2B, HDAC3), ubiquitin-linkage-specific immunoprecipitation, pharmacological SLC25A1/ACLY inhibition in vitro and in vivo The EMBO journal High 39881208
2024 ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial DNA leakage, which activates the cGAS-STING innate immune pathway; this drives PD-L1 upregulation but also enables enhanced anti-tumor immunity when combined with PD-L1 blockade. Pharmacological and genetic ACLY inhibition, lipid peroxidation assays, mitochondrial damage quantification, cGAS-STING pathway activation assays, immunocompetent mouse tumor models, B cell/T cell depletion Science advances High 38055816
2024 CD8 T cell responses depend on cytosolic acetyl-CoA produced by ACLY from citrate; ablation of ACLY triggers a compensatory ACSS2-dependent acetate pathway that fuels both TCA cycle and cytosolic acetyl-CoA production, maintaining histone acetylation and chromatin accessibility at effector gene loci. Conditional ACLY and ACSS2 knockout mice, in vivo infection models, acetate tracing, ATAC-seq chromatin accessibility, histone acetylation ChIP-seq, T cell functional assays The Journal of experimental medicine High 39150482
2025 A novel ACLY inhibitor EVT0185 is converted to its CoA thioester (EVT0185-CoA) in liver by SLC27A2; cryo-EM structural analysis demonstrates that EVT0185-CoA directly occupies the CoA-binding site of ACLY; genetic ACLY inhibition in hepatocytes and tumors reduces HCC lesions, and this antitumor effect is associated with increased CXCL13, tumor-infiltrating B cells, and tertiary lymphoid structures, and is abolished by B cell depletion. Cryo-electron microscopy structure, pharmacological and genetic (hepatocyte-specific KO) ACLY inhibition, transcriptomic/spatial profiling, B cell depletion experiments, three mouse models of MASH-HCC Nature High 40739358
2023 Nuclear ACLY (Acly) undergoes translocation from cytoplasm to nucleus in hepatocytes during ischemia-reperfusion (IR); nuclear Acly supplies acetyl-CoA for H3K9 acetylation and activates Foxa2-mediated protective gene expression; cytosolic ACLY does not provide this protection; steatosis disrupts nuclear translocation, worsening IR injury. Hepatocyte-specific ACLY knockout mice, nuclear fractionation, CUT&RUN assay, RNA-seq, H3K9 acetylation ChIP, Rspondin overexpression rescue, hypoxia-reperfusion cell model Hepatology (Baltimore, Md.) High 37983829
2025 Alpha-synuclein A53T mutation and elevated α-Syn expression activate ACLY, increasing cytoplasmic acetyl-CoA; this promotes LKB1 acetylation, which inhibits AMPK and causes cytoplasmic retention of p300, lowering histone acetylation and increasing acetylation of cytoplasmic p300 substrates (e.g., raptor), leading to mTORC1 hyperactivation and impaired autophagy; ACLY inhibitors rescue these phenotypes in PD neurons, organoids, zebrafish, and mice. Human neurons, organoids, zebrafish and mouse PD models; acetyl-CoA quantification; LKB1/AMPK/p300/raptor acetylation assays; mTORC1 activity assays; ACLY inhibitor treatment rescue in multiple models Neuron High 40262613
2019 ACLY inhibition in airway epithelial cells reverses PM2.5-induced epithelial-mesenchymal transition (EMT), migration, and invasion; PM2.5 exposure upregulates ACLY in vitro and in vivo, and ACLY knockdown restores epithelial marker expression and reduces mesenchymal markers. PM2.5 exposure model (30 passages), metabolomics, qRT-PCR, western blot, migration/invasion assays, siRNA knockdown, murine lung tissue analysis Ecotoxicology and environmental safety Medium 30343145
2020 VHL promotes ubiquitination and degradation of PPARγ, which is the transcription factor that drives ACLY expression by binding to the PPRE element on the ACLY promoter; VHL deficiency thus upregulates ACLY via PPARγ stabilization, promoting lipid accumulation. Co-IP, ubiquitination assays in vitro and in vivo, promoter-binding assays (PPRE identification), adenovirus-mediated VHL overexpression in db/db mice Metabolism: clinical and experimental Medium 32589900
2023 Cytoplasmic ENDOG releases Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY signaling axis, resulting in acetyl-CoA production and lipid synthesis; loss of ENDOG suppresses this axis and reduces lipid synthesis in hepatocytes. Competitive binding assays (ENDOG vs Rictor for 14-3-3γ), mTORC2/AKT activation assays, acetyl-CoA measurement, ENDOG knockout mice with HFD Nature communications Medium 37794041
2024 ACLY inhibition reduces de novo lipogenesis in cardiac fibroblasts, limiting fatty acid supply for proliferation and decreasing H3K9 and H3K27 acetylation at promoters of fibrotic genes, thereby suppressing TGF-β-induced cardiac fibrosis. Acly gene silencing (AAV9-shRNA), pharmacological inhibition, 13C-glucose stable isotope tracing, ChIP for H3K9ac/H3K27ac at fibrotic gene promoters, histological fibrosis scoring in angiotensin II/phenylephrine mouse model Hypertension (Dallas, Tex. : 1979) Medium 40047081
2025 VDR transcriptionally represses ACLY expression by binding to its promoter (confirmed by ChIP-qPCR and dual luciferase assay); VDR-mediated ACLY downregulation preserves the Nrf2/Keap1 antioxidant system and reduces lipid peroxidation in diabetic nephropathy. ChIP-qPCR, dual luciferase promoter assays, VDR knockout mice, ACLY overexpression rescue, ROS/MDA/4-HNE quantification FASEB journal Medium 39302807
2024 In proinflammatory macrophages, the long ACLY isoform (ACLY L) undergoes protein lactylation at K918/K995, which reduces its metabolic activity; the short isoform (ACLY S), lacking these sites, is constitutively more active; RBM25 deficiency shifts expression toward ACLY S, enhancing acetyl-CoA production and inflammatory gene expression. Mass spectrometry-based lactylation mapping, isoform-specific expression constructs, metabolic flux and acetyl-CoA assays, RBM25 KO mice phenotyping Cellular & molecular immunology Medium 39251781
2024 SIRT1 impairs H3K27 acetylation at the ACLY promoter, thereby repressing ACLY transcription and maintaining fatty acid oxidation; the SP1 transcription factor regulates this pathway by directly controlling SIRT1 expression, forming an SP1/SIRT1/ACLY axis in renal ischemia-reperfusion. ChIP assay (H3K27ac at ACLY promoter), RNA-seq, SIRT1 KO mice, AAV-mediated SIRT1 overexpression, bioinformatics International immunopharmacology Medium 38608473
2021 SIRT6 controls nuclear levels of ACLY; SIRT6 inactivation causes accumulation of nuclear ACLY, increases nuclear acetyl-CoA pools, and drives locus-specific histone acetylation to upregulate cancer cell adhesion and migration genes. SIRT6 inactivation in cancer cells, nuclear ACLY quantification by fractionation, acetyl-CoA measurement, ChIP for histone acetylation at target gene loci, migration/invasion assays Genes Medium 34573442
2023 FBXW7 (an E3 ubiquitin ligase) interacts with ACLY to promote its ubiquitination and proteasomal degradation; this interaction is activated downstream of NF-κB signaling following LPCAT1 knockdown in ccRCC, thereby reducing fatty acid production. RNA-seq, lipidomics, NF-κB pathway activation assays, Co-IP (FBXW7-ACLY interaction), ACLY protein stability assays International journal of biological sciences Medium 39781455
2024 HIF-1A acts as a transcription factor that binds the ACLY promoter under hypoxia (confirmed by ChIP assay) and upregulates ACLY expression, driving gastric cancer progression and peritoneal metastasis. ChIP assay for HIF-1A binding to ACLY promoter, hypoxia treatment, qPCR/western blot, in vitro and in vivo functional assays Cell cycle (Georgetown, Tex.) Medium 38009671
2022 IKKβ phosphorylation by the natural compound Dehy promotes K48-linked ubiquitination and proteasomal degradation of ACLY, reducing fatty acid synthesis in gastric cancer cells; IKKβ is the direct molecular target of Dehy as demonstrated by biolayer interferometry. Biolayer interferometry (direct binding), IKKβ phosphorylation assays, ACLY ubiquitination/degradation assays, network pharmacology, PDX in vivo model Journal of advanced research Medium 38295877
2025 Pharmacological inhibition of ACLY by the natural compound isoginkgetin (ISOGK) directly binds ACLY protein (confirmed by SPR and CETSA), inhibits its enzymatic activity in vitro, and reduces hepatic cholesterol/lipid synthesis and atherosclerosis in vivo; the lipid-lowering effects are abolished when hepatic ACLY is knocked down, confirming ACLY as the on-target mechanism. Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), enzymatic activity assays, GalNAc-siRNA hepatic ACLY knockdown, atherosclerosis mouse/hamster models Theranostics High 40225566
2019 ACLY inhibition by bempedoic acid requires its activation to a CoA thioester by liver-specific ACSL1; this prodrug mechanism restricts ACLY inhibition to the liver, avoiding skeletal muscle effects, and the active form competitively inhibits ACLY to reduce hepatic acetyl-CoA and upregulate LDL receptor expression. Described in review context with mechanistic basis from clinical and preclinical pharmacology studies; biochemical characterization of prodrug activation and competitive inhibition Progress in lipid research Medium 31499095
2022 The ACLY inhibitor 326E is converted to its CoA thioester (326E-CoA), which inhibits ACLY enzymatic activity with IC50 = 5.31 μmol/L in vitro; this reduces de novo lipogenesis and increases cholesterol efflux, improving hyperlipidemia and atherosclerosis in hamsters, rhesus monkeys, and ApoE-/- mice. In vitro ACLY enzymatic activity assay (IC50 measurement), de novo lipogenesis assays, cholesterol efflux assays, pharmacokinetics, chronic animal model studies Acta pharmaceutica Sinica. B High 36873173
2020 In CD8+ T cells, Acly inhibition during early activation specifically reduces H3K9 acetylation at the IRF4 promoter (without affecting global H3ac) and downregulates IRF4 expression, impairing early activation markers and shifting cellular metabolism toward fatty acid uptake over glucose uptake. Acly inhibitor (BMS303141) in polyclonal murine CD8+ T cell activation, promoter-specific ChIP for H3ac, IRF4 expression analysis, metabolic substrate uptake assays Cytometry. Part A Medium 33325591

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Mendelian Randomization Study of ACLY and Cardiovascular Disease. The New England journal of medicine 267 30865797
2017 Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination. Molecular cell 238 28689661
2019 ACLY facilitates colon cancer cell metastasis by CTNNB1. Journal of experimental & clinical cancer research : CR 190 31511060
2018 ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. European journal of medicinal chemistry 185 30195238
2019 ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: An updated review. Progress in lipid research 179 31499095
2015 ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Current drug targets 123 25537655
2023 Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation. Science advances 113 38055816
1995 Intrinsic properties of ACL and MCL cells and their responses to growth factors. Medicine and science in sports and exercise 77 7658945
2013 Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34+ cell sheets for ACL reconstruction. Biomaterials 76 23632324
2006 Canine ACL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 75 16453340
2016 Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 72 27248322
2017 ACL injury reduces satellite cell abundance and promotes fibrogenic cell expansion within skeletal muscle. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 66 27935172
2020 Osteoarthritis and ACL Reconstruction-Myths and Risks. Current reviews in musculoskeletal medicine 65 31894466
2019 Adipocyte ACLY Facilitates Dietary Carbohydrate Handling to Maintain Metabolic Homeostasis in Females. Cell reports 63 31141698
2021 IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell death & disease 56 34075028
2020 Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice. Metabolism: clinical and experimental 56 32888949
2022 Nanog mediated by FAO/ACLY signaling induces cellular dormancy in colorectal cancer cells. Cell death & disease 54 35177584
2023 Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. Journal of experimental & clinical cancer research : CR 52 37122003
2020 ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis. Genes & diseases 52 34179312
2022 Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation. Autophagy 50 35404187
2003 Differential expression of fatty acid synthase genes, Acl, Fat and Kas, in Capsicum fruit. Journal of experimental botany 50 12810854
2021 Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 47 34155695
2019 Pediatric ACL Tears: Natural History. Journal of pediatric orthopedics 46 31169648
2020 ACLY: A biomarker of recurrence in breast cancer. Pathology, research and practice 45 32825949
2021 ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell death & disease 42 34839358
2021 Recommendations for Movement Re-training After ACL Reconstruction. Sports medicine (Auckland, N.Z.) 41 33840081
2015 ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate. PLoS genetics 41 26452058
2024 Nobiletin targets SREBP1/ACLY to induce autophagy-dependent cell death of gastric cancer cells through PI3K/Akt/mTOR signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 40 38547624
2022 Canine ACL reconstruction with an injectable hydroxyapatite/collagen paste for accelerated healing of tendon-bone interface. Bioactive materials 40 35633878
2021 Regulation on Citrate Influx and Metabolism through Inhibiting SLC13A5 and ACLY: A Novel Mechanism Mediating the Therapeutic Effects of Curcumin on NAFLD. Journal of agricultural and food chemistry 40 34323067
2020 Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression. Metabolism: clinical and experimental 40 32589900
2016 Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes. Molecular & cellular proteomics : MCP 40 27067055
2014 Histological features of the ACL remnant in partial tears. The Knee 38 25112212
2021 Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer. Cancer letters 35 33991616
2024 Dehydrocostus lactone suppresses gastric cancer progression by targeting ACLY to inhibit fatty acid synthesis and autophagic flux. Journal of advanced research 34 38295877
2023 ACL and HAT1 form a nuclear module to acetylate histone H4K5 and promote cell proliferation. Nature communications 34 37277331
2022 ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective. Expert opinion on therapeutic patents 33 35436171
2022 Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia. Acta pharmaceutica Sinica. B 32 36873173
2023 Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress. Nature communications 30 37794041
2022 ACLY inhibitors induce apoptosis and potentiate cytotoxic effects of sorafenib in thyroid cancer cells. Endocrine 30 35761130
2022 LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and metastasis through miR-655/ACLY signal. Cancer cell international 30 36309693
2024 ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. The Journal of experimental medicine 28 39150482
2023 Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice. Cell reports. Medicine 28 37729871
2002 Cell outgrowth from the human ACL in vitro: regional variation and response to TGF-beta1. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 28 12168681
2022 Targeted inhibition of ACLY expression to reverse the resistance of sorafenib in hepatocellular carcinoma. Journal of Cancer 26 35154461
2022 Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion. Oncology reports 26 36562384
2021 Functional and molecular adaptations of quadriceps and hamstring muscles to blood flow restricted training in patients with ACL rupture. Scandinavian journal of medicine & science in sports 26 33837592
2019 ACLY (ATP Citrate Lyase) Mediates Radioresistance in Head and Neck Squamous Cell Carcinomas and is a Novel Predictive Radiotherapy Biomarker. Cancers 26 31817870
2018 Inhibition of ATP citrate lyase (ACLY) protects airway epithelia from PM2.5-induced epithelial-mesenchymal transition. Ecotoxicology and environmental safety 26 30343145
2023 LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation. Molecular cancer research : MCR 25 37409966
2023 ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis. Journal of translational medicine 25 37620891
2009 Expression of MMPs and TIMPs family in human ACL and MCL fibroblasts. Connective tissue research 24 19212848
2015 Bridge-enhanced ACL repair: A review of the science and the pathway through FDA investigational device approval. Annals of biomedical engineering 23 25631206
2025 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation. The EMBO journal 22 39881208
2025 ACLY inhibition promotes tumour immunity and suppresses liver cancer. Nature 22 40739358
2024 RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring. Cellular & molecular immunology 22 39251781
2019 ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile. Metabolites 22 31775252
2019 Bacterial DNA is associated with tunnel widening in failed ACL reconstructions. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 21 30810788
2016 Generation of stem cell-based bioartificial anterior cruciate ligament (ACL) grafts for effective ACL rupture repair. Stem cell research 20 27217303
2021 Shear strain and inflammation-induced fixed charge density loss in the knee joint cartilage following ACL injury and reconstruction: A computational study. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 19 34533840
2010 Fibrin concentration affects ACL fibroblast proliferation and collagen synthesis. The Knee 18 20080411
2009 ACL prosthesis: any promise for the future? Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 18 19915821
2023 Synovial Fluid Proteomics From Serial Aspirations of ACL-Injured Knees Identifies Candidate Biomarkers. The American journal of sports medicine 17 37191559
2023 BCAT2 promotes melanoma progression by activating lipogenesis via the epigenetic regulation of FASN and ACLY expressions. Cellular and molecular life sciences : CMLS 17 37801083
2022 ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer. Cell death & disease 17 36241648
2022 Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear-Resultant Quadriceps Atrophy. The American journal of sports medicine 17 36475881
2020 ACLY is the novel signaling target of PIP2/PIP3 and Lyn in acute myeloid leukemia. Heliyon 17 32420483
2014 ACL injuries and stem cell therapy. Archives of orthopaedic and trauma surgery 17 25073617
2024 ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo. Gut 16 38176897
2024 Morusin, a novel inhibitor of ACLY, induces mitochondrial apoptosis in hepatocellular carcinoma cells through ROS-mediated mitophagy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 39341077
2024 RBM15 promotes lipogenesis and malignancy in gastric cancer by regulating N6-Methyladenosine modification of ACLY mRNA in an IGF2BP2-dependent manner. Biochimica et biophysica acta. Molecular and cell biology of lipids 16 39549859
2022 Co-interventions with Clostridium butyricum and soluble dietary fiber targeting the gut microbiota improve MAFLD via the Acly/Nrf2/NF-κB signaling pathway. Food & function 16 35543143
2021 Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation. Genes 16 34573442
2009 Coordinated expression of MMPs and TIMPs in rat knee intra-articular tissues after ACL injury. Connective tissue research 16 19863390
2025 Herbal-based Xuebijing injection ameliorated vascular endothelial dysfunction via inhibiting ACLY/MYB/RIG-I axis in sepsis-associated lung injury. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 40088739
2023 Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging. Communications biology 14 36890357
2023 Active post-transcriptional regulation and ACLY-mediated acetyl-CoA synthesis as a pivotal target of Shuang-Huang-Sheng-Bai formula for lung adenocarcinoma treatment. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 36933457
2011 VEGF receptor mRNA expression by ACL fibroblasts is associated with functional healing of the ACL. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 14 21331648
2024 SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 13 38426936
2023 Nuclear Acly protects the liver from ischemia-reperfusion injury. Hepatology (Baltimore, Md.) 13 37983829
2025 Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacological research 12 40127788
2025 A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY. Theranostics 12 40225566
2024 Vitamin D receptor alleviates lipid peroxidation in diabetic nephropathy by regulating ACLY/Nrf2/Keap1 pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 39302807
2022 Mechano Growth Factor Accelerates ACL Repair and Improves Cell Mobility of Mechanically Injured Human ACL Fibroblasts by Targeting Rac1-PAK1/2 and RhoA-ROCK1 Pathways. International journal of molecular sciences 12 35457148
2021 Application of Stem Cell Therapy for ACL Graft Regeneration. Stem cells international 12 34381504
1994 The apolipoprotein C2-linked (Acl) gene: a new gene within the mouse apolipoprotein e-c1-c2 gene cluster. Genomics 12 8088778
2025 HIF-2α/LPCAT1 orchestrates the reprogramming of lipid metabolism in ccRCC by modulating the FBXW7-mediated ubiquitination of ACLY. International journal of biological sciences 11 39781455
2023 Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis. Drug metabolism and disposition: the biological fate of chemicals 11 37684055
2020 Acly promotes metabolic reprogramming and induction of IRF4 during early CD8+ T cell activation. Cytometry. Part A : the journal of the International Society for Analytical Cytology 11 33325591
2025 Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition. Neuron 10 40262613
2024 The SP1/SIRT1/ACLY signaling axis mediates fatty acid oxidation in renal ischemia-reperfusion-induced renal fibrosis. International immunopharmacology 10 38608473
2023 Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer. International journal of molecular sciences 10 37958642
2023 ACLY promotes gastric tumorigenesis and accelerates peritoneal metastasis of gastric cancer regulated by HIF-1A. Cell cycle (Georgetown, Tex.) 10 38009671
2020 Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study. Journal of biomolecular structure & dynamics 10 32448086
2025 ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation. Hypertension (Dallas, Tex. : 1979) 9 40047081
2023 IL-6 induces periostin production in human ACL remnants: a possible mechanism causing post-traumatic osteoarthritis. Journal of orthopaedic surgery and research 9 37919719
2022 Evaluating the diagnostic pathway for acute ACL injuries in trauma centres: a systematic review. BMC musculoskeletal disorders 9 35799147
2020 Evaluation of a bioengineered ACL matrix's osteointegration with BMP-2 supplementation. PloS one 9 31910231
2018 Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4). PloS one 9 30192824
2004 2-ClATP exerts anti-tumoural actions not mediated by P2 receptors in neuronal and glial cell lines. Biochemical pharmacology 9 14757162

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