Affinage

ACLY

ATP-citrate synthase · UniProt P53396

Length
1101 aa
Mass
120.8 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACLY is a homotetrameric citrate lyase that cleaves citrate into acetyl-CoA and oxaloacetate, serving as the principal bridge between mitochondrial TCA-cycle metabolism and cytosolic/nuclear acetyl-CoA pools required for de novo lipogenesis, cholesterol biosynthesis, protein acetylation, and chromatin remodeling. In the cytosol, ACLY-derived acetyl-CoA sustains fatty acid synthesis and regulates ferroptosis susceptibility by maintaining FSP1 acetylation at K168, preventing its ubiquitin-dependent degradation (PMID:39881208); its activity is stimulated by AKT-mediated S455 phosphorylation and Lyn-mediated tyrosine phosphorylation, and attenuated by multiple E3 ligase-dependent degradation routes (CUL3-KLHL25, Hrd1/ERAD, NEDD4, and SQSTM1/p62-mediated selective autophagy) as well as SIRT2-dependent deacetylation (PMID:27664236, PMID:32888949, PMID:35404187, PMID:38426936). In the nucleus, ACLY translocates in response to DNA damage (ATM/AKT) or ischemia-reperfusion and supplies acetyl-CoA for histone acetylation that directs DNA repair pathway choice toward homologous recombination, controls inflammatory and immune gene programs in macrophages and T cells, and regulates hepatoprotective transcription (PMID:28689661, PMID:37983829, PMID:39150482). ACLY loss in CD8+ T cells triggers a compensatory ACSS2-dependent acetate pathway that partially sustains histone acetylation and chromatin accessibility at effector loci, and hyperactivation of ACLY by pathogenic α-synuclein drives mTORC1-dependent autophagy impairment in Parkinson's disease neuronal models (PMID:39150482, PMID:40262613).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2016 High

    Establishing that ACLY is a regulated target of the ubiquitin-proteasome system answered how cells limit lipid synthesis post-translationally: CUL3-KLHL25 ubiquitinates and degrades ACLY to restrain tumor lipogenesis.

    Evidence Reciprocal Co-IP, ubiquitination assays, and xenograft rescue with ACLY inhibitor

    PMID:27664236

    Open questions at the time
    • Whether KLHL25 degron on ACLY is mapped to specific residues
    • Tissue-specific relevance of CUL3-KLHL25 outside tumor context
    • Interplay with other E3 ligases targeting ACLY
  2. 2016 High

    Linking AKT-dependent S455 phosphorylation of ACLY to nuclear histone acetylation in T cells established that cytokine-driven signaling controls chromatin state through metabolic enzyme activation.

    Evidence Nuclear phosphoproteomics in IL-2-stimulated T cells, ACLY depletion, histone acetylation and gene expression analysis

    PMID:27067055

    Open questions at the time
    • Whether specific acetyltransferases mediate ACLY-dependent histone marks in T cells
    • Contribution of alternative acetyl-CoA sources in this context
  3. 2017 High

    Demonstrating that ATM/AKT-driven nuclear phosphorylation of ACLY at S455 fuels local histone acetylation at DNA double-strand breaks resolved how metabolic state influences repair pathway choice between HR and NHEJ.

    Evidence ACLY silencing, phospho-site mutagenesis, 53BP1/BRCA1 recruitment imaging, PARP inhibitor sensitivity

    PMID:28689661

    Open questions at the time
    • Identity of the acetyltransferase depositing acetylation at break sites
    • Mechanism governing ACLY nuclear import
    • Whether nuclear ACLY is retained at breaks via protein-protein interactions
  4. 2020 High

    Identification of Hrd1/ERAD and NEDD4 as additional E3 ligases for ACLY, together with the finding that ARHGEF3 protects ACLY from NEDD4 by reducing K17/K86 acetylation, revealed a multi-layered ubiquitin-acetylation crosstalk controlling ACLY stability and lipogenesis.

    Evidence Co-IP/MS, ubiquitination assays, acetylation site mapping, in vivo lipogenesis measurement in db/db mice

    PMID:32888949 PMID:36241648

    Open questions at the time
    • Structural basis for how K17/K86 acetylation promotes NEDD4 recognition
    • Relative quantitative contribution of each E3 ligase in different tissues
  5. 2020 High

    Discovery that PIP2/PIP3 bind ACLY and that Lyn phosphorylates multiple ACLY tyrosine residues to stimulate catalytic activity established a direct signaling-to-metabolism link in AML cells beyond the known AKT-S455 axis.

    Evidence Direct binding assays, domain mapping, site-directed mutagenesis of six tyrosine residues, enzyme activity assays

    PMID:32420483

    Open questions at the time
    • Whether Lyn-mediated ACLY phosphorylation occurs in non-AML cell types
    • Structural details of PIP2 binding at the CoA domain
  6. 2020 Medium

    Showing that ACLY physically interacts with β-catenin to promote its nuclear translocation and transcriptional activity expanded ACLY's role beyond metabolic enzyme to a scaffolding partner in Wnt signaling-driven metastasis.

    Evidence Co-IP, ACLY-deficient colon cancer cell lines, migration/invasion assays, in vivo mouse metastasis model

    PMID:31511060

    Open questions at the time
    • No reciprocal validation of direct binding
    • Whether the interaction is catalytic-activity-dependent or structural
    • Independent replication needed
  7. 2021 High

    Demonstrating ACLY nuclear translocation during osteoclast differentiation, where it drives GCN5-dependent H3 acetylation and Rac1 transcription, generalized the nuclear ACLY paradigm to bone remodeling.

    Evidence ACLY knockdown and inhibitor, nuclear translocation imaging, GCN5 epistasis, RNA-seq, OVX mouse model

    PMID:34155695

    Open questions at the time
    • Signal controlling ACLY nuclear translocation in osteoclasts
    • Whether other acetyltransferases besides GCN5 contribute
  8. 2022 High

    Identifying K63-linked ubiquitination of ACLY and its recognition by SQSTM1/p62 for selective autophagic degradation established a non-proteasomal route for ACLY turnover, with physiological importance in oocyte maturation.

    Evidence Ubiquitin linkage analysis, autophagy inhibition, metabolomics, citrate rescue in granulosa cells

    PMID:35404187

    Open questions at the time
    • Identity of the E3 ligase catalyzing K63-linked ubiquitination
    • Whether autophagic ACLY degradation operates in other cell types
  9. 2022 Medium

    Connecting ACLY to the SIRT2 deacetylase and the Tip60-HIF-1α acetylation axis in macrophages positioned ACLY acetyl-CoA output as a regulatory node in inflammatory signaling.

    Evidence SIRT2 inhibitor/Co-IP in ESCC, ACLY inhibition with Tip60/HIF-1α readouts in macrophages

    PMID:35713568 PMID:38426936

    Open questions at the time
    • Specific ACLY acetylation sites regulated by SIRT2 remain unmapped in macrophages
    • Independent replication of Tip60-HIF-1α axis link
  10. 2023 High

    Revealing that nuclear ACLY translocation during hepatic ischemia-reperfusion drives H3K9 acetylation and Foxa2 activation established a hepatoprotective epigenetic circuit, and that steatosis disrupts this translocation explained increased IR injury in fatty liver.

    Evidence Hepatocyte-specific Acly KO mice, CUT&RUN, RNA-seq, nuclear fractionation, Rspondin rescue

    PMID:37983829

    Open questions at the time
    • Mechanism by which steatosis impairs nuclear translocation
    • Whether Foxa2 is the sole downstream target
  11. 2023 High

    Demonstrating that ACLY inhibition causes PUFA peroxidation and mitochondrial DNA leakage activating cGAS-STING and PD-L1 upregulation revealed an unintended immunosuppressive consequence of targeting ACLY in tumors.

    Evidence Genetic and pharmacological ACLY inhibition, cGAS KO rescue, dietary PUFA supplementation, immunocompetent tumor models

    PMID:38055816

    Open questions at the time
    • Whether this immunosuppressive effect is universal across tumor types
    • Optimal combination strategy to counter PD-L1 upregulation
  12. 2024 High

    Genetic epistasis between ACLY and ACSS2 in CD8+ T cells proved that acetate-derived acetyl-CoA serves as a compensatory fuel for histone acetylation and effector gene accessibility when citrate-derived acetyl-CoA is lost.

    Evidence ACLY/ACSS2 single and double genetic ablation, ATAC-seq, metabolic tracing, in vivo infection models

    PMID:39150482

    Open questions at the time
    • Whether ACSS2 compensation is sufficient long-term in chronic infection or cancer
    • Locus specificity of ACLY- vs. ACSS2-dependent acetylation
  13. 2024 High

    Identification of RBM25-mediated alternative splicing of ACLY exon 14 generating isoforms differentially susceptible to lactylation at K918/K995 established a new layer of isoform-specific post-translational regulation in inflammatory macrophages.

    Evidence RIP, splicing reporters, lactylation site mapping/mutagenesis, metabolic flux, macrophage-specific RBM25 KO mice

    PMID:39251781

    Open questions at the time
    • Whether ACLY isoform ratio changes in human inflammatory diseases
    • Identity of the lactylation writer
  14. 2025 High

    Placing ACLY upstream of FSP1 acetylation/stability via the SLC25A1→ACLY→KAT2B→FSP1(K168ac) axis defined a metabolic checkpoint for ferroptosis susceptibility.

    Evidence CRISPR screen, K168 mutagenesis, KAT2B/HDAC3 perturbation, in vivo ferroptosis assays

    PMID:39881208

    Open questions at the time
    • Tissue-specific relevance of this axis beyond cell lines tested
    • Whether other anti-ferroptotic proteins are similarly regulated by ACLY-derived acetyl-CoA
  15. 2025 High

    Cryo-EM of ACLY bound to EVT0185-CoA defined the structural basis of CoA-competitive inhibition, and hepatocyte-specific ACLY KO combined with this inhibitor revealed that ACLY loss promotes anti-tumor immunity via CXCL13 and B cell infiltration in MASH-HCC.

    Evidence Cryo-EM structure, hepatocyte-specific ACLY KO, spatial transcriptomics, B cell depletion in MASH-HCC models

    PMID:40739358

    Open questions at the time
    • Whether CXCL13-mediated B cell recruitment generalizes beyond MASH-HCC
    • Structural basis of ACLY tetramer allostery
  16. 2025 High

    Demonstrating that pathogenic α-synuclein activates ACLY → p300 → LKB1 acetylation → AMPK inhibition → mTORC1 hyperactivation → autophagy impairment positioned ACLY as a druggable node in Parkinson's disease pathogenesis.

    Evidence iPSC-derived neurons, organoids, zebrafish and mouse PD models, ACLY inhibitor rescue, raptor acetylation assays

    PMID:40262613

    Open questions at the time
    • Whether ACLY inhibition is neuroprotective in human PD
    • Mechanism by which α-synuclein activates ACLY

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism controlling signal-dependent nuclear import/export of ACLY remains undefined — no nuclear localization signal, transport receptor, or retention factor has been identified.
  • No NLS or nuclear transport receptor identified
  • No structural model of full-length human ACLY tetramer with post-translational modifications mapped
  • Quantitative contribution of each degradation route (CUL3-KLHL25, Hrd1, NEDD4, autophagy) in different tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016829 lyase activity 6 GO:0042393 histone binding 4
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-4839726 Chromatin organization 6 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
CTNNB1FABP7KLHL25LYNNEDD4SIRT2SQSTM1SYVN1

Evidence

Reading pass · 27 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 damage, facilitating histone acetylation at double-strand break sites, impairing 53BP1 localization, enabling BRCA1 recruitment, and promoting DNA repair by homologous recombination; ACLY phosphorylation and nuclear localization are necessary for this role. Loss-of-function (ACLY silencing), phosphorylation analysis, nuclear localization imaging, 53BP1/BRCA1 recruitment assays, cell viability upon PARP inhibition Molecular cell High 28689661
2016 The CUL3-KLHL25 ubiquitin ligase complex interacts with ACLY through the adaptor protein KLHL25 to ubiquitinate and degrade ACLY, thereby negatively regulating lipid synthesis, cell proliferation, and tumor growth. Co-immunoprecipitation, ubiquitination assays in cells, xenograft tumor models, ACLY inhibitor rescue experiments Genes & development High 27664236
2020 Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacts with and ubiquitinates ACLY, reducing its protein level, suppressing acetyl-CoA production, and inhibiting lipogenesis. Co-IP-based mass spectrometry, co-IP immunoblotting, acetyl-CoA measurement, lipogenesis assay, adenovirus-mediated overexpression in db/db mice Metabolism: clinical and experimental High 32888949
2016 ACLY is phosphorylated on serine 455 in T lymphocytes upon IL-2-driven AKT activation; this phosphorylation is required for enhanced histone acetylation and induction of cell cycle regulating genes, linking cytokine signaling to T-cell proliferation. Nuclear phosphoproteomics (mass spectrometry), ACLY depletion/inactivation, histone acetylation measurement, gene expression analysis Molecular & cellular proteomics High 27067055
2022 ACLY is selectively decorated with K63-linked ubiquitin chains and recognized by the autophagy receptor SQSTM1/p62 for selective autophagic degradation in granulosa cells, maintaining citrate homeostasis to promote oocyte maturation. Co-immunoprecipitation, ubiquitin linkage analysis, genetic/pharmacological autophagy inhibition, metabolomics, exogenous citrate rescue Autophagy High 35404187
2025 SLC25A1 exports citrate from mitochondria to the cytosol where ACLY converts it to acetyl-CoA; this acetyl-CoA sustains FSP1 acetylation at K168 (by KAT2B) and prevents its K29-linked ubiquitin-dependent proteasomal degradation, thereby regulating ferroptosis susceptibility. CRISPR-Cas9 screen, Co-IP, ubiquitination assays, acetylation site mutagenesis, in vitro and in vivo ferroptosis assays, pharmacological inhibition of SLC25A1 and ACLY The EMBO journal High 39881208
2025 A novel ACLY inhibitor (EVT0185) is converted to a CoA thioester (EVT0185-CoA) in the liver by SLC27A2; cryo-EM structural analysis reveals EVT0185-CoA directly interacts with the CoA-binding site of ACLY, reducing tumor burden in MASH-HCC models and promoting tumour immunity through CXCL13 upregulation and B cell infiltration. Cryo-EM structural analysis, genetic hepatocyte-specific ACLY knockout, phenotypic small-molecule screening, transcriptomic/spatial profiling, B cell depletion experiments Nature High 40739358
2024 CD8+ T cell responses to infection depend on acetyl-CoA derived from citrate via ACLY; ablation of ACLY triggers a compensatory acetate-dependent pathway for acetyl-CoA production via ACSS2, which impacts histone acetylation and chromatin accessibility at effector gene loci. Genetic ACLY ablation in CD8+ T cells, ACSS2 genetic ablation, chromatin accessibility assays (ATAC-seq), histone acetylation measurement, in vivo infection models The Journal of experimental medicine High 39150482
2021 RANKL-induced osteoclast differentiation activates ACLY in an AKT-dependent manner; ACLY translocates to the nucleus, increases nucleocytosolic acetyl-CoA and histone H3 acetylation (GCN5-dependent), and transcriptionally upregulates Rac1 to regulate osteoclast cytoskeleton organization and differentiation. ACLY knockdown, ACLY inhibitor (BMS-303141), nuclear translocation imaging, histone acetylation measurement, RNA-sequencing, GCN5 knockdown/overexpression, OVX mouse model Journal of bone and mineral research High 34155695
2020 FABP7 interacts with ACLY in the nucleus of astrocytes, regulating nuclear acetyl-CoA metabolism and histone acetylation, which epigenetically controls caveolin-1 expression. Co-immunoprecipitation, FABP7-KO primary astrocytes, gain-of-function in NIH-3T3 cells, nuclear fractionation Molecular neurobiology Medium 32812201
2020 ACLY interacts with and stabilizes CTNNB1 (β-catenin) protein, and the ACLY-CTNNB1 complex promotes CTNNB1 translocation from cytoplasm to nucleus, enhancing its transcriptional activity and promoting colon cancer cell migration and invasion. Western blots, Co-immunoprecipitation, ACLY-deficient cell lines, migration/invasion assays, in vivo mouse metastasis model Journal of experimental & clinical cancer research Medium 31511060
2020 PIP2 and PIP3 bind to ACLY (PIP2 at the CoA-binding domain) in AML cells; the Src-family kinase Lyn phosphorylates six tyrosine residues of ACLY (including Y682, Y252, Y227 in catalytic, citrate-binding, and ATP-binding domains), stimulating its enzymatic activity, acetyl-CoA synthesis, and phospholipid/histone acetylation. Direct binding assays, domain mapping, site-directed mutagenesis of tyrosine residues, kinase inhibitor treatment, ACLY enzyme activity assay, acetyl-CoA measurement Heliyon High 32420483
2016 ACLY-dependent fatty acid synthesis maintains AR protein levels in castration-resistant prostate cancer cells through an ACLY-AMPK-AR feedback loop; combined ACLY inhibition and AR antagonism promotes energetic stress, AMPK activation, ER stress, and apoptosis. ACLY inhibition (pharmacological), AR antagonist combination, AMPK activation measurement, fatty acid rescue experiments, gene expression correlation Oncotarget Medium 27248322
2023 ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, triggering mitochondrial DNA leakage that activates the cGAS-STING innate immune pathway, leading to PD-L1 upregulation and immunosuppression. Pharmacological and genetic ACLY inhibition, PUFA supplementation, mitochondrial damage assays, cGAS-STING pathway readouts, immunocompetent mouse tumor models, PD-L1 checkpoint assays Science advances High 38055816
2024 RBM25 directly binds ACLY pre-mRNA and mediates skipping of exon 14, generating two ACLY isoforms (Acly Long and Acly Short); in proinflammatory macrophages, Acly L undergoes protein lactylation at K918/K995, which affects substrate affinity and metabolic activity, whereas Acly S (lacking this site) does not, altering glycolysis and acetyl-CoA production for epigenetic remodeling. RNA binding protein immunoprecipitation, splicing reporter assays, lactylation site mapping/mutagenesis, metabolic flux analysis, macrophage-specific RBM25 knockout mice Cellular & molecular immunology High 39251781
2022 SIRT2 interacts with ACLY in esophageal squamous cell carcinoma cells and deacetylates ACLY protein; SIRT2 inhibition increases ACLY acetylation and inhibits cancer cell proliferation and migration, while ACLY overexpression partially reverses these effects. Co-immunoprecipitation, acetylation assays, SIRT2 inhibitor (AGK2), ACLY overexpression rescue, in vitro proliferation/migration assays, xenograft model Journal of cellular and molecular medicine Medium 38426936
2022 ARHGEF3 enhances the protein stability of ACLY by reducing its acetylation on K17 and K86, leading to dissociation between ACLY and its E3 ligase NEDD4, independently of ARHGEF3's GEF activity. Co-immunoprecipitation, acetylation site mapping (K17/K86), NEDD4 interaction assay, ARHGEF3 knockdown/overexpression, xenograft model Cell death & disease Medium 36241648
2023 Upon ER stress, IRE1α phosphorylates SEC63 at T537, which then stabilizes ACLY protein, increasing acetyl-CoA and lipid biosynthesis; SEC63 also coordinates with nuclear ACLY to epigenetically upregulate Snail1 expression, promoting HCC metastasis. GST pull-down, immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, immunofluorescence, RNA-sequencing Journal of experimental & clinical cancer research Medium 37122003
2023 Nuclear ACLY in hepatocytes translocates to the nucleus during ischemia-reperfusion, fueling nuclear acetyl-CoA production, enhancing H3K9 acetylation, and activating the Foxa2 signaling pathway to confer hepatoprotection; steatosis disrupts this nuclear translocation, increasing IR vulnerability. Hepatocyte-specific Acly knockout mice, CUT&RUN assay, RNA-sequencing, nuclear fractionation/localization imaging, Rspondin overexpression rescue Hepatology High 37983829
2022 In macrophages, LPS stimulation activates the ACLY-Tip60 pathway to enhance HIF-1α acetylation, contributing to HIF-1α protein stabilization and exacerbation of LPS-induced inflammation. ACLY inhibition, Tip60 pathway analysis, HIF-1α acetylation measurement, NAD+/SIRT1 pathway analysis FASEB journal Medium 35713568
2021 SIRT6 controls nuclear levels of ACLY protein; inactivation of SIRT6 in cancer cells leads to accumulation of nuclear ACLY, increases nuclear acetyl-CoA pools, and drives locus-specific histone acetylation of cancer cell adhesion and migration genes, promoting tumor invasiveness. SIRT6 inactivation, nuclear ACLY quantification, nuclear acetyl-CoA measurement, histone acetylation at specific loci, invasion assays Genes Medium 34573442
2025 PD-causing A53T α-synuclein mutation and elevated α-synuclein expression activate ACLY, increasing cytoplasmic acetyl-CoA that activates p300 and increases LKB1 acetylation, inhibiting AMPK, driving cytoplasmic p300 accumulation, mTORC1 hyperactivation via raptor acetylation, and consequent autophagy impairment; ACLY inhibitors rescue these phenotypes. Human iPSC-derived neurons, organoids, zebrafish and mouse PD models, acetyl-CoA measurement, LKB1/AMPK/mTORC1 signaling assays, ACLY inhibitor treatment, raptor acetylation measurement Neuron High 40262613
2024 ACLY inhibition increases CD8+ T cell ACSS2-mediated acetate utilization for both TCA cycle substrates and cytosolic acetyl-CoA; this acetate-dependent compensatory pathway maintains histone acetylation and chromatin accessibility at effector gene loci when ACLY is absent. Genetic ACLY/ACSS2 double ablation, ATAC-seq, histone acetylation, metabolic tracing, in vivo infection models The Journal of experimental medicine High 39150482
2020 NONO promotes ACLY mRNA stability in the nucleus via interaction with ACLY mRNA (along with SFPQ as a heterodimer), enhancing fatty acid biosynthesis and HCC progression. RNA-binding protein immunoprecipitation sequencing (RIP-seq), chromatin immunoprecipitation, Co-immunoprecipitation/mass spectrometry, nuclear fractionation, subcutaneous xenograft model Cancer cell international Medium 32884448
2021 Cytoplasmic cytosol endonuclease G (ENDOG) releases Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in increased acetyl-CoA production and lipid synthesis. Co-immunoprecipitation, mTORC2-AKT-ACLY axis signaling assays, loss-of-function studies, high-fat diet mouse model Nature communications Medium 37794041
2021 VHL directly interacts with and promotes ubiquitination of PPARγ, leading to PPARγ degradation and downregulation of ACLY transcription (PPARγ binds the PPRE cis-regulatory element on the ACLY promoter), thereby reducing de novo lipid synthesis. Co-immunoprecipitation, ubiquitination assays in vitro and in vivo, PPRE promoter binding assay, adenovirus-mediated VHL overexpression in db/db mice Metabolism: clinical and experimental Medium 32589900
2024 ACLY maintains FSP1 acetylation at K168 by supplying cytosolic acetyl-CoA; acetylation of K168 by KAT2B prevents FSP1 proteasomal degradation via K29-linked ubiquitin chains, while HDAC3 deacetylates FSP1 at the same site. CRISPR screen, acetylation site mutagenesis (K168), Co-IP, ubiquitin linkage-type analysis, KAT2B/HDAC3 genetic perturbation, ferroptosis assays in vitro and in vivo The EMBO journal High 39881208

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 264 30865797
2017 Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination. Molecular cell 232 28689661
2019 ACLY facilitates colon cancer cell metastasis by CTNNB1. Journal of experimental & clinical cancer research : CR 187 31511060
2018 ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. European journal of medicinal chemistry 181 30195238
2019 ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: An updated review. Progress in lipid research 176 31499095
2015 ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Current drug targets 121 25537655
2023 Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation. Science advances 108 38055816
2016 Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes & development 102 27664236
2020 m6A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1. Frontiers in oncology 94 33134163
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
2016 Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 71 27248322
2020 Osteoarthritis and ACL Reconstruction-Myths and Risks. Current reviews in musculoskeletal medicine 63 31894466
2013 Why menisci show higher healing rate when repaired during ACL reconstruction? Growth factors release can be the explanation. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 61 24146050
2011 Matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament (ACL) rupture. Scandinavian journal of medicine & science in sports 59 21410539
2020 Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice. Metabolism: clinical and experimental 56 32888949
2021 IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell death & disease 54 34075028
2022 Nanog mediated by FAO/ACLY signaling induces cellular dormancy in colorectal cancer cells. Cell death & disease 52 35177584
2021 Pharmacological induction of mesenchymal-epithelial transition via inhibition of H2S biosynthesis and consequent suppression of ACLY activity in colon cancer cells. Pharmacological research 52 33484818
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 51 37122003
2020 ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis. Genes & diseases 51 34179312
2003 Differential expression of fatty acid synthase genes, Acl, Fat and Kas, in Capsicum fruit. Journal of experimental botany 50 12810854
2022 Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation. Autophagy 48 35404187
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 45 34155695
1999 Differences in cellular properties and responses to growth factors between human ACL and MCL cells. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 45 10436277
2019 Pediatric ACL Tears: Natural History. Journal of pediatric orthopedics 44 31169648
2021 ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell death & disease 41 34839358
2021 Recommendations for Movement Re-training After ACL Reconstruction. Sports medicine (Auckland, N.Z.) 40 33840081
2016 Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes. Molecular & cellular proteomics : MCP 40 27067055
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 38 34323067
2020 Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression. Metabolism: clinical and experimental 38 32589900
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 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 34 38547624
2022 ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective. Expert opinion on therapeutic patents 31 35436171
2022 Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia. Acta pharmaceutica Sinica. B 31 36873173
2024 Dehydrocostus lactone suppresses gastric cancer progression by targeting ACLY to inhibit fatty acid synthesis and autophagic flux. Journal of advanced research 30 38295877
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
2020 FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes. Molecular neurobiology 30 32812201
2014 Tendon-to-bone healing using autologous bone marrow-derived mesenchymal stem cells in ACL reconstruction without a tibial bone tunnel-A histological study-. Muscles, ligaments and tendons journal 28 25332936
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 LPS stimulation stabilizes HIF-1α by enhancing HIF-1α acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 35713568
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
2018 Inhibition of ATP citrate lyase (ACLY) protects airway epithelia from PM2.5-induced epithelial-mesenchymal transition. Ecotoxicology and environmental safety 26 30343145
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 25 37729871
2022 Targeted inhibition of ACLY expression to reverse the resistance of sorafenib in hepatocellular carcinoma. Journal of Cancer 25 35154461
2011 Analysis of sequential cytokine release after ACL reconstruction. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 25 21445592
2022 Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion. Oncology reports 24 36562384
2015 Bridge-enhanced ACL repair: A review of the science and the pathway through FDA investigational device approval. Annals of biomedical engineering 23 25631206
2024 ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. The Journal of experimental medicine 22 39150482
2004 Tensile forces attenuate estrogen-stimulated collagen synthesis in the ACL. Biochemical and biophysical research communications 22 15094400
2023 ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis. Journal of translational medicine 21 37620891
2019 Bacterial DNA is associated with tunnel widening in failed ACL reconstructions. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 21 30810788
2019 ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile. Metabolites 21 31775252
2025 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation. The EMBO journal 20 39881208
2024 RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring. Cellular & molecular immunology 20 39251781
2001 Absolute concentrations of mRNA for type I and type VI collagen in the canine meniscus in normal and ACL-deficient knee joints obtained by RNase protection assay. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20 11518275
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 18 34533840
2020 NONO promotes hepatocellular carcinoma progression by enhancing fatty acids biosynthesis through interacting with ACLY mRNA. Cancer cell international 18 32884448
2016 Generation of stem cell-based bioartificial anterior cruciate ligament (ACL) grafts for effective ACL rupture repair. Stem cell research 18 27217303
2010 Fibrin concentration affects ACL fibroblast proliferation and collagen synthesis. The Knee 18 20080411
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
2021 An O-GlcNAcylomic Approach Reveals ACLY as a Potential Target in Sepsis in the Young Rat. International journal of molecular sciences 17 34502162
2014 ACL injuries and stem cell therapy. Archives of orthopaedic and trauma surgery 17 25073617
2023 Synovial Fluid Proteomics From Serial Aspirations of ACL-Injured Knees Identifies Candidate Biomarkers. The American journal of sports medicine 16 37191559
2022 Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion. Oxidative medicine and cellular longevity 16 35602106
2022 ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer. Cell death & disease 16 36241648
2020 ACLY is the novel signaling target of PIP2/PIP3 and Lyn in acute myeloid leukemia. Heliyon 16 32420483
2009 Coordinated expression of MMPs and TIMPs in rat knee intra-articular tissues after ACL injury. Connective tissue research 16 19863390
2025 ACLY inhibition promotes tumour immunity and suppresses liver cancer. Nature 15 40739358
2024 ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo. Gut 15 38176897
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 15 39549859
2022 Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear-Resultant Quadriceps Atrophy. The American journal of sports medicine 15 36475881
2021 Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation. Genes 15 34573442
2024 Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis. Cancer science 14 38494608
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
2023 Cartilage fragments combined with BMSCs-Derived exosomes can promote tendon-bone healing after ACL reconstruction. Materials today. Bio 14 37810754
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 14 35543143
2004 Epidermal growth factor differentially affects integrin-mediated adhesion and proliferation of ACL and MCL fibroblasts. Biorheology 14 15090682
2024 SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 13 38426936
2024 Morusin, a novel inhibitor of ACLY, induces mitochondrial apoptosis in hepatocellular carcinoma cells through ROS-mediated mitophagy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 13 39341077
2025 A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY. Theranostics 12 40225566
2023 Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging. Communications biology 12 36890357
2023 Nuclear Acly protects the liver from ischemia-reperfusion injury. Hepatology (Baltimore, Md.) 12 37983829
2021 Application of Stem Cell Therapy for ACL Graft Regeneration. Stem cells international 12 34381504
2010 The profile of MMP and TIMP in injured rat ACL. Molecular & cellular biomechanics : MCB 12 20936743
2020 Comparative Metabolites and Citrate-Degrading Enzymes Activities in Citrus Fruits Reveal the Role of Balance between ACL and Cyt-ACO in Metabolite Conversions. Plants (Basel, Switzerland) 11 32164290
2020 Single bout of vibration-induced hamstrings fatigue reduces quadriceps inhibition and coactivation of knee muscles after anterior cruciate ligament (ACL) reconstruction. Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology 11 32942109
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 10 40088739
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 10 37684055
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
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 10 33325591
2025 Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition. Neuron 9 40262613
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 9 39302807
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
2015 Sulfasalazine attenuates ACL transection and medial menisectomy-induced cartilage destruction by inhibition of cystine/glutamate antiporter. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 9 26466556
2004 2-ClATP exerts anti-tumoural actions not mediated by P2 receptors in neuronal and glial cell lines. Biochemical pharmacology 9 14757162