{"gene":"ACLY","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":2017,"finding":"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.","method":"Phosphorylation-site mutagenesis, nuclear fractionation/localization experiments, siRNA knockdown with HR/NHEJ reporter assays, Co-IP, chromatin immunofluorescence","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, fractionation, repair pathway assays, Co-IP) in a single rigorous study with clear mechanistic readouts","pmids":["28689661"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Mass spectrometry-based nuclear phosphoproteomics, siRNA knockdown, pharmacological ACLY inhibition, histone acetylation quantification, cell-cycle/proliferation assays","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased phosphoproteomic discovery confirmed by orthogonal functional assays (KD, inhibitor, histone acetylation, proliferation)","pmids":["27067055"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP/mass spectrometry, co-immunoblotting, acetyl-CoA measurement, lipogenesis assays, adenovirus-mediated overexpression in db/db mice","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP-MS identification confirmed by reciprocal co-IP, functional rescue in vitro and in vivo","pmids":["32888949"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP with ubiquitin-linkage-specific antibodies, autophagy flux assays, SQSTM1 pulldown, granulosa cell autophagy inhibition/ablation, metabolomics, oocyte maturation scoring","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific ubiquitin linkage identified by Co-IP, receptor-cargo interaction demonstrated, functional consequence (oocyte maturation) confirmed with multiple orthogonal methods","pmids":["35404187"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis between ACLY and GCN5 established, nuclear translocation documented, in vivo validation in OVX model, multiple orthogonal methods","pmids":["34155695"],"is_preprint":false},{"year":2020,"finding":"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.","method":"PIP-binding assays (domain mapping), in vitro kinase assay with Lyn/Src, mass spectrometry phosphosite identification, PI3K/Lyn inhibitor treatment with enzymatic activity readouts","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and phosphosite identification by MS, enzymatic activity confirmed pharmacologically; single lab","pmids":["32420483"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP, western blot, migration/invasion assays in ACLY-deficient cell lines, in vivo mouse colon metastasis model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction shown, functional rescue/loss-of-function with phenotypic readout, single lab","pmids":["31511060"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genome-wide shRNA screen, metabolomics, α-ketoglutarate supplementation rescue, ETV4 knockdown epistasis, transcriptional profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen plus metabolomic validation, epistasis with ETV4, metabolite rescue, multiple orthogonal methods","pmids":["26452058"],"is_preprint":false},{"year":2016,"finding":"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.","method":"ACLY inhibitor treatment, AMPK activation measurement, AR protein/mRNA quantification, fatty acid rescue experiments, ER stress assays, gene expression correlation in human tumor data","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic ACLY inhibition with fatty acid rescue establishes the feedback loop; single lab, no reconstitution","pmids":["27248322"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Nuclear fractionation, phospho-site analysis, ChIP, siRNA knockdown, AKT inhibitor, promoter-binding assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear localization linked to histone acetylation and gene expression changes; transcriptional regulation by STAT3 confirmed by ChIP; single lab","pmids":["33991616"],"is_preprint":false},{"year":2023,"finding":"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.","method":"GST pulldown, immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assays, immunofluorescence, RNA-seq, transwell assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (GST pulldown, IP-MS, phosphorylation/ubiquitination assays) in single lab","pmids":["37122003"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, acetylation immunoblotting, SIRT2 inhibitor (AGK2) treatment, ACLY overexpression rescue, proliferation/migration assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and acetylation status confirmed by Co-IP/immunoblot, epistatic rescue experiment; single lab","pmids":["38426936"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, acetylation site mutagenesis (K17/K86), NEDD4 interaction assays, ARHGEF3 GEF-dead mutant, proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetylation sites identified with mutagenesis, E3 ligase interaction mapped, GEF-independent mechanism confirmed; single lab","pmids":["36241648"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, acetylation/ubiquitination assays, ACLY-BP knockdown/overexpression, lipid quantification, tumor growth assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction established, PTM (acetylation protecting from ubiquitination) characterized, functional rescue; single lab","pmids":["37409966"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RNA-seq splice isoform analysis, mass spectrometry-based lactylation site mapping, RBM25 knockdown, isoform-specific overexpression, metabolic flux assays, ChIP","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splice isoforms characterized, lactylation sites identified by MS, functional consequences of isoform expression tested; single lab","pmids":["39251781"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR screen validated by orthogonal biochemical methods; acetylation writer/eraser and ubiquitin linkage identified; in vivo confirmation","pmids":["39881208"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological inhibition with cGAS-dependent rescue and in vivo immunocompetent models, multiple orthogonal mechanistic readouts","pmids":["38055816"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional ACLY and ACSS2 knockout mice, in vivo infection models, acetate tracing, ATAC-seq chromatin accessibility, histone acetylation ChIP-seq, T cell functional assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO epistasis in vivo, chromatin accessibility and acetylation linked to ACLY/ACSS2 activity, multiple orthogonal methods","pmids":["39150482"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional inhibitor bound, genetic KO validated in multiple in vivo models, immune mechanism confirmed by depletion; multiple orthogonal methods across independent models","pmids":["40739358"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Hepatocyte-specific ACLY knockout mice, nuclear fractionation, CUT&RUN assay, RNA-seq, H3K9 acetylation ChIP, Rspondin overexpression rescue, hypoxia-reperfusion cell model","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model, nuclear fractionation with functional distinction from cytosolic ACLY, CUT&RUN identifying target genes, multiple orthogonal methods","pmids":["37983829"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism validated across multiple model systems (human neurons, organoids, zebrafish, mice) with orthogonal biochemical readouts and pharmacological rescue","pmids":["40262613"],"is_preprint":false},{"year":2019,"finding":"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.","method":"PM2.5 exposure model (30 passages), metabolomics, qRT-PCR, western blot, migration/invasion assays, siRNA knockdown, murine lung tissue analysis","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics identified citrate upregulation, ACLY KD reverses EMT phenotype in vitro and in vivo; single lab","pmids":["30343145"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP, ubiquitination assays in vitro and in vivo, promoter-binding assays (PPRE identification), adenovirus-mediated VHL overexpression in db/db mice","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct VHL-PPARγ interaction and ubiquitination demonstrated, promoter element mapped; single lab","pmids":["32589900"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Competitive binding assays (ENDOG vs Rictor for 14-3-3γ), mTORC2/AKT activation assays, acetyl-CoA measurement, ENDOG knockout mice with HFD","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding competition and pathway activation established; in vivo KO model; single lab, no reconstitution","pmids":["37794041"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isotope tracing confirms metabolic flux, ChIP links ACLY to specific histone marks at fibrotic gene promoters, in vivo KD; single lab","pmids":["40047081"],"is_preprint":false},{"year":2025,"finding":"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.","method":"ChIP-qPCR, dual luciferase promoter assays, VDR knockout mice, ACLY overexpression rescue, ROS/MDA/4-HNE quantification","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter occupancy confirmed by ChIP and luciferase, in vivo KO model, overexpression rescue; single lab","pmids":["39302807"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Mass spectrometry-based lactylation mapping, isoform-specific expression constructs, metabolic flux and acetyl-CoA assays, RBM25 KO mice phenotyping","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lactylation sites mapped by MS, isoform functional difference demonstrated; single lab","pmids":["39251781"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay (H3K27ac at ACLY promoter), RNA-seq, SIRT1 KO mice, AAV-mediated SIRT1 overexpression, bioinformatics","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes SIRT1-mediated histone mark at ACLY promoter; in vivo KO model; single lab","pmids":["38608473"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SIRT6 inactivation in cancer cells, nuclear ACLY quantification by fractionation, acetyl-CoA measurement, ChIP for histone acetylation at target gene loci, migration/invasion assays","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation, acetyl-CoA measurement, and locus-specific ChIP establish SIRT6-ACLY-histone acetylation axis; single lab","pmids":["34573442"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA-seq, lipidomics, NF-κB pathway activation assays, Co-IP (FBXW7-ACLY interaction), ACLY protein stability assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrates FBXW7-ACLY interaction, degradation confirmed; pathway context established by RNA-seq and lipidomics; single lab","pmids":["39781455"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay for HIF-1A binding to ACLY promoter, hypoxia treatment, qPCR/western blot, in vitro and in vivo functional assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter occupancy confirmed by ChIP; functional consequences shown in vitro and in vivo; single lab","pmids":["38009671"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Biolayer interferometry (direct binding), IKKβ phosphorylation assays, ACLY ubiquitination/degradation assays, network pharmacology, PDX in vivo model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by BLI, phosphorylation-dependent ubiquitination established; single lab","pmids":["38295877"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), enzymatic activity assays, GalNAc-siRNA hepatic ACLY knockdown, atherosclerosis mouse/hamster models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding confirmed by two orthogonal biophysical methods, enzymatic activity assay, on-target validation by hepatic KD reversing drug effect in vivo","pmids":["40225566"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Described in review context with mechanistic basis from clinical and preclinical pharmacology studies; biochemical characterization of prodrug activation and competitive inhibition","journal":"Progress in lipid research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical competitive inhibition mechanism and prodrug activation established in prior literature, summarized with in vivo validation; review synthesis","pmids":["31499095"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vitro ACLY enzymatic activity assay (IC50 measurement), de novo lipogenesis assays, cholesterol efflux assays, pharmacokinetics, chronic animal model studies","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic IC50 assay, CoA thioester mechanism confirmed, multiple in vivo animal species; single lab","pmids":["36873173"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Acly inhibitor (BMS303141) in polyclonal murine CD8+ T cell activation, promoter-specific ChIP for H3ac, IRF4 expression analysis, metabolic substrate uptake assays","journal":"Cytometry. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — locus-specific ChIP links ACLY activity to IRF4 promoter acetylation; metabolic shift confirmed; single lab","pmids":["33325591"],"is_preprint":false}],"current_model":"ACLY is a cytosolic homotetrameric enzyme that cleaves citrate and CoA to generate acetyl-CoA and oxaloacetate (consuming ATP), serving as the primary cytosolic acetyl-CoA source linking mitochondrial TCA-cycle carbon to fatty acid/cholesterol synthesis and histone/protein acetylation; its activity is regulated by AKT-mediated S455 phosphorylation, acetylation (maintained by ACLY-BP, reversed by SIRT2; targeting ACLY for ubiquitin-proteasomal degradation via NEDD4 or FBXW7), lactylation of splice-isoform-specific sites, and K63-linked ubiquitination for selective autophagic degradation via SQSTM1/p62; nuclear-translocated ACLY locally supplies acetyl-CoA to histone acetyltransferases (including GCN5/KAT2B) for locus-specific H3 acetylation governing DNA repair pathway choice (HR vs. NHEJ), immune gene programs, fibrotic gene expression, and osteoclast differentiation, while cytosolic ACLY fuels de novo lipogenesis and, via the SLC25A1-ACLY axis, sustains FSP1 acetylation to suppress ferroptosis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2015,"claim":"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","pmids":["26452058"],"confidence":"High","gaps":["Mechanism by which α-ketoglutarate epigenetically suppresses ETV4 not resolved","Did not address nuclear vs cytosolic ACLY pools"]},{"year":2016,"claim":"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","pmids":["27067055","27248322"],"confidence":"High","gaps":["Direct demonstration of nuclear acetyl-CoA generation not yet shown","Which HATs use ACLY-derived acetyl-CoA not defined"]},{"year":2017,"claim":"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","pmids":["28689661"],"confidence":"High","gaps":["HAT partner at DSB sites not identified","Quantitative contribution of local vs bulk acetyl-CoA unclear"]},{"year":2020,"claim":"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","pmids":["32420483","32888949"],"confidence":"Medium","gaps":["PIP2/PIP3 binding effect on activity from single lab","Structural basis of tyrosine-phosphorylation-driven activation not resolved"]},{"year":2021,"claim":"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","pmids":["34155695","34573442","33991616"],"confidence":"High","gaps":["Mechanism of ACLY nuclear import not defined","How SIRT6 controls nuclear ACLY levels mechanistically unclear"]},{"year":2022,"claim":"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","pmids":["36241648","38426936","35404187"],"confidence":"Medium","gaps":["Cross-talk between acetylation, K48 and K63 ubiquitination on the same residues not integrated","Most interactions from single labs without reciprocal validation"]},{"year":2023,"claim":"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","pmids":["37983829","37122003","37794041","39781455","37409966"],"confidence":"High","gaps":["Signals determining nuclear vs cytosolic partitioning in different tissues not unified","Several upstream regulators characterized in single contexts"]},{"year":2024,"claim":"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","pmids":["39150482","39251781","38055816","40047081","33325591"],"confidence":"High","gaps":["Functional consequence of lactylation from single lab","Determinants of compensatory ACSS2 engagement across tissues not defined"]},{"year":2025,"claim":"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 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biophysica acta. 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Part A : the journal of the International Society for Analytical Cytology","url":"https://pubmed.ncbi.nlm.nih.gov/33325591","citation_count":11,"is_preprint":false},{"pmid":"37684055","id":"PMC_37684055","title":"Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis.","date":"2023","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/37684055","citation_count":11,"is_preprint":false},{"pmid":"40262613","id":"PMC_40262613","title":"Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition.","date":"2025","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/40262613","citation_count":10,"is_preprint":false},{"pmid":"38009671","id":"PMC_38009671","title":"ACLY promotes gastric tumorigenesis and accelerates peritoneal metastasis of gastric cancer regulated by HIF-1A.","date":"2023","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/38009671","citation_count":10,"is_preprint":false},{"pmid":"37958642","id":"PMC_37958642","title":"Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37958642","citation_count":10,"is_preprint":false},{"pmid":"38608473","id":"PMC_38608473","title":"The SP1/SIRT1/ACLY signaling axis mediates fatty acid oxidation in renal ischemia-reperfusion-induced renal fibrosis.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38608473","citation_count":10,"is_preprint":false},{"pmid":"32448086","id":"PMC_32448086","title":"Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study.","date":"2020","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/32448086","citation_count":10,"is_preprint":false},{"pmid":"37919719","id":"PMC_37919719","title":"IL-6 induces periostin production in human ACL remnants: a possible mechanism causing post-traumatic osteoarthritis.","date":"2023","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/37919719","citation_count":9,"is_preprint":false},{"pmid":"40047081","id":"PMC_40047081","title":"ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation.","date":"2025","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/40047081","citation_count":9,"is_preprint":false},{"pmid":"14757162","id":"PMC_14757162","title":"2-ClATP exerts anti-tumoural actions not mediated by P2 receptors in neuronal and glial cell lines.","date":"2004","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/14757162","citation_count":9,"is_preprint":false},{"pmid":"35799147","id":"PMC_35799147","title":"Evaluating the diagnostic pathway for acute ACL injuries in trauma centres: a systematic review.","date":"2022","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/35799147","citation_count":9,"is_preprint":false},{"pmid":"31910231","id":"PMC_31910231","title":"Evaluation of a bioengineered ACL matrix's osteointegration with BMP-2 supplementation.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31910231","citation_count":9,"is_preprint":false},{"pmid":"30192824","id":"PMC_30192824","title":"Anticardiolipin (aCL) in sera from periodontitis subjects activate Toll-like receptor 4 (TLR4).","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30192824","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54353,"output_tokens":9249,"usd":0.150897,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19703,"output_tokens":3862,"usd":0.097532,"stage2_stop_reason":"end_turn"},"total_usd":0.248429,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation-site mutagenesis, nuclear fractionation/localization experiments, siRNA knockdown with HR/NHEJ reporter assays, Co-IP, chromatin immunofluorescence\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, fractionation, repair pathway assays, Co-IP) in a single rigorous study with clear mechanistic readouts\",\n      \"pmids\": [\"28689661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based nuclear phosphoproteomics, siRNA knockdown, pharmacological ACLY inhibition, histone acetylation quantification, cell-cycle/proliferation assays\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased phosphoproteomic discovery confirmed by orthogonal functional assays (KD, inhibitor, histone acetylation, proliferation)\",\n      \"pmids\": [\"27067055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP/mass spectrometry, co-immunoblotting, acetyl-CoA measurement, lipogenesis assays, adenovirus-mediated overexpression in db/db mice\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP-MS identification confirmed by reciprocal co-IP, functional rescue in vitro and in vivo\",\n      \"pmids\": [\"32888949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP with ubiquitin-linkage-specific antibodies, autophagy flux assays, SQSTM1 pulldown, granulosa cell autophagy inhibition/ablation, metabolomics, oocyte maturation scoring\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific ubiquitin linkage identified by Co-IP, receptor-cargo interaction demonstrated, functional consequence (oocyte maturation) confirmed with multiple orthogonal methods\",\n      \"pmids\": [\"35404187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis between ACLY and GCN5 established, nuclear translocation documented, in vivo validation in OVX model, multiple orthogonal methods\",\n      \"pmids\": [\"34155695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"PIP-binding assays (domain mapping), in vitro kinase assay with Lyn/Src, mass spectrometry phosphosite identification, PI3K/Lyn inhibitor treatment with enzymatic activity readouts\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and phosphosite identification by MS, enzymatic activity confirmed pharmacologically; single lab\",\n      \"pmids\": [\"32420483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, western blot, migration/invasion assays in ACLY-deficient cell lines, in vivo mouse colon metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction shown, functional rescue/loss-of-function with phenotypic readout, single lab\",\n      \"pmids\": [\"31511060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide shRNA screen, metabolomics, α-ketoglutarate supplementation rescue, ETV4 knockdown epistasis, transcriptional profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen plus metabolomic validation, epistasis with ETV4, metabolite rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26452058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"ACLY inhibitor treatment, AMPK activation measurement, AR protein/mRNA quantification, fatty acid rescue experiments, ER stress assays, gene expression correlation in human tumor data\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic ACLY inhibition with fatty acid rescue establishes the feedback loop; single lab, no reconstitution\",\n      \"pmids\": [\"27248322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclear fractionation, phospho-site analysis, ChIP, siRNA knockdown, AKT inhibitor, promoter-binding assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization linked to histone acetylation and gene expression changes; transcriptional regulation by STAT3 confirmed by ChIP; single lab\",\n      \"pmids\": [\"33991616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"GST pulldown, immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assays, immunofluorescence, RNA-seq, transwell assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (GST pulldown, IP-MS, phosphorylation/ubiquitination assays) in single lab\",\n      \"pmids\": [\"37122003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, acetylation immunoblotting, SIRT2 inhibitor (AGK2) treatment, ACLY overexpression rescue, proliferation/migration assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and acetylation status confirmed by Co-IP/immunoblot, epistatic rescue experiment; single lab\",\n      \"pmids\": [\"38426936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, acetylation site mutagenesis (K17/K86), NEDD4 interaction assays, ARHGEF3 GEF-dead mutant, proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetylation sites identified with mutagenesis, E3 ligase interaction mapped, GEF-independent mechanism confirmed; single lab\",\n      \"pmids\": [\"36241648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, acetylation/ubiquitination assays, ACLY-BP knockdown/overexpression, lipid quantification, tumor growth assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction established, PTM (acetylation protecting from ubiquitination) characterized, functional rescue; single lab\",\n      \"pmids\": [\"37409966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq splice isoform analysis, mass spectrometry-based lactylation site mapping, RBM25 knockdown, isoform-specific overexpression, metabolic flux assays, ChIP\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splice isoforms characterized, lactylation sites identified by MS, functional consequences of isoform expression tested; single lab\",\n      \"pmids\": [\"39251781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR screen validated by orthogonal biochemical methods; acetylation writer/eraser and ubiquitin linkage identified; in vivo confirmation\",\n      \"pmids\": [\"39881208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological inhibition with cGAS-dependent rescue and in vivo immunocompetent models, multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"38055816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional ACLY and ACSS2 knockout mice, in vivo infection models, acetate tracing, ATAC-seq chromatin accessibility, histone acetylation ChIP-seq, T cell functional assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO epistasis in vivo, chromatin accessibility and acetylation linked to ACLY/ACSS2 activity, multiple orthogonal methods\",\n      \"pmids\": [\"39150482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional inhibitor bound, genetic KO validated in multiple in vivo models, immune mechanism confirmed by depletion; multiple orthogonal methods across independent models\",\n      \"pmids\": [\"40739358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Hepatocyte-specific ACLY knockout mice, nuclear fractionation, CUT&RUN assay, RNA-seq, H3K9 acetylation ChIP, Rspondin overexpression rescue, hypoxia-reperfusion cell model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model, nuclear fractionation with functional distinction from cytosolic ACLY, CUT&RUN identifying target genes, multiple orthogonal methods\",\n      \"pmids\": [\"37983829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism validated across multiple model systems (human neurons, organoids, zebrafish, mice) with orthogonal biochemical readouts and pharmacological rescue\",\n      \"pmids\": [\"40262613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"PM2.5 exposure model (30 passages), metabolomics, qRT-PCR, western blot, migration/invasion assays, siRNA knockdown, murine lung tissue analysis\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics identified citrate upregulation, ACLY KD reverses EMT phenotype in vitro and in vivo; single lab\",\n      \"pmids\": [\"30343145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, ubiquitination assays in vitro and in vivo, promoter-binding assays (PPRE identification), adenovirus-mediated VHL overexpression in db/db mice\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct VHL-PPARγ interaction and ubiquitination demonstrated, promoter element mapped; single lab\",\n      \"pmids\": [\"32589900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Competitive binding assays (ENDOG vs Rictor for 14-3-3γ), mTORC2/AKT activation assays, acetyl-CoA measurement, ENDOG knockout mice with HFD\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding competition and pathway activation established; in vivo KO model; single lab, no reconstitution\",\n      \"pmids\": [\"37794041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isotope tracing confirms metabolic flux, ChIP links ACLY to specific histone marks at fibrotic gene promoters, in vivo KD; single lab\",\n      \"pmids\": [\"40047081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-qPCR, dual luciferase promoter assays, VDR knockout mice, ACLY overexpression rescue, ROS/MDA/4-HNE quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter occupancy confirmed by ChIP and luciferase, in vivo KO model, overexpression rescue; single lab\",\n      \"pmids\": [\"39302807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based lactylation mapping, isoform-specific expression constructs, metabolic flux and acetyl-CoA assays, RBM25 KO mice phenotyping\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lactylation sites mapped by MS, isoform functional difference demonstrated; single lab\",\n      \"pmids\": [\"39251781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay (H3K27ac at ACLY promoter), RNA-seq, SIRT1 KO mice, AAV-mediated SIRT1 overexpression, bioinformatics\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes SIRT1-mediated histone mark at ACLY promoter; in vivo KO model; single lab\",\n      \"pmids\": [\"38608473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 inactivation in cancer cells, nuclear ACLY quantification by fractionation, acetyl-CoA measurement, ChIP for histone acetylation at target gene loci, migration/invasion assays\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation, acetyl-CoA measurement, and locus-specific ChIP establish SIRT6-ACLY-histone acetylation axis; single lab\",\n      \"pmids\": [\"34573442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, lipidomics, NF-κB pathway activation assays, Co-IP (FBXW7-ACLY interaction), ACLY protein stability assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrates FBXW7-ACLY interaction, degradation confirmed; pathway context established by RNA-seq and lipidomics; single lab\",\n      \"pmids\": [\"39781455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay for HIF-1A binding to ACLY promoter, hypoxia treatment, qPCR/western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter occupancy confirmed by ChIP; functional consequences shown in vitro and in vivo; single lab\",\n      \"pmids\": [\"38009671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Biolayer interferometry (direct binding), IKKβ phosphorylation assays, ACLY ubiquitination/degradation assays, network pharmacology, PDX in vivo model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by BLI, phosphorylation-dependent ubiquitination established; single lab\",\n      \"pmids\": [\"38295877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), enzymatic activity assays, GalNAc-siRNA hepatic ACLY knockdown, atherosclerosis mouse/hamster models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding confirmed by two orthogonal biophysical methods, enzymatic activity assay, on-target validation by hepatic KD reversing drug effect in vivo\",\n      \"pmids\": [\"40225566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Described in review context with mechanistic basis from clinical and preclinical pharmacology studies; biochemical characterization of prodrug activation and competitive inhibition\",\n      \"journal\": \"Progress in lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical competitive inhibition mechanism and prodrug activation established in prior literature, summarized with in vivo validation; review synthesis\",\n      \"pmids\": [\"31499095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ACLY enzymatic activity assay (IC50 measurement), de novo lipogenesis assays, cholesterol efflux assays, pharmacokinetics, chronic animal model studies\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic IC50 assay, CoA thioester mechanism confirmed, multiple in vivo animal species; single lab\",\n      \"pmids\": [\"36873173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Acly inhibitor (BMS303141) in polyclonal murine CD8+ T cell activation, promoter-specific ChIP for H3ac, IRF4 expression analysis, metabolic substrate uptake assays\",\n      \"journal\": \"Cytometry. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — locus-specific ChIP links ACLY activity to IRF4 promoter acetylation; metabolic shift confirmed; single lab\",\n      \"pmids\": [\"33325591\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACLY is a cytosolic homotetrameric enzyme that cleaves citrate and CoA to generate acetyl-CoA and oxaloacetate (consuming ATP), serving as the primary cytosolic acetyl-CoA source linking mitochondrial TCA-cycle carbon to fatty acid/cholesterol synthesis and histone/protein acetylation; its activity is regulated by AKT-mediated S455 phosphorylation, acetylation (maintained by ACLY-BP, reversed by SIRT2; targeting ACLY for ubiquitin-proteasomal degradation via NEDD4 or FBXW7), lactylation of splice-isoform-specific sites, and K63-linked ubiquitination for selective autophagic degradation via SQSTM1/p62; nuclear-translocated ACLY locally supplies acetyl-CoA to histone acetyltransferases (including GCN5/KAT2B) for locus-specific H3 acetylation governing DNA repair pathway choice (HR vs. NHEJ), immune gene programs, fibrotic gene expression, and osteoclast differentiation, while cytosolic ACLY fuels de novo lipogenesis and, via the SLC25A1-ACLY axis, sustains FSP1 acetylation to suppress ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#15, #17]. 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 [#0], cytokine-driven cell-cycle gene expression in T cells [#1], osteoclast differentiation via GCN5-dependent H3 acetylation of Rac1 [#4], and Foxa2-mediated protective programs during hepatic ischemia-reperfusion [#19]. 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 [#33, #34], with cryo-EM confirming inhibitor occupancy of the CoA-binding site [#18]. 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 [#2, #3, #11, #15] — and transcriptionally by stress- and metabolism-responsive factors [#22, #30]. Through the SLC25A1–ACLY axis, ACLY-derived acetyl-CoA sustains FSP1 acetylation to suppress ferroptosis [#15], and ACLY activity broadly couples metabolic state to chromatin accessibility at effector gene loci [#17, #35]. ACLY also acts in disease contexts including alpha-synuclein-driven mTORC1 hyperactivation in Parkinson neurons [#20] and innate-immune activation via cGAS-STING upon its inhibition [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that ACLY-dependent metabolic flux shapes cell fate under hypoxia, beyond simply supplying lipids, by controlling oncogenic transcription via metabolite levels.\",\n      \"evidence\": \"Genome-wide shRNA screen with metabolomics and \\u03b1-ketoglutarate rescue in cancer cells\",\n      \"pmids\": [\"26452058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which \\u03b1-ketoglutarate epigenetically suppresses ETV4 not resolved\", \"Did not address nuclear vs cytosolic ACLY pools\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked cytokine signaling to ACLY function by showing AKT-driven S455 phosphorylation enables ACLY to support histone acetylation and proliferation in T cells.\",\n      \"evidence\": \"Nuclear phosphoproteomics, knockdown, inhibitor, and proliferation assays in CD4+ T cells; AMPK-AR feedback loop in prostate cancer\",\n      \"pmids\": [\"27067055\", \"27248322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of nuclear acetyl-CoA generation not yet shown\", \"Which HATs use ACLY-derived acetyl-CoA not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-site mutagenesis, nuclear fractionation, HR/NHEJ reporters, chromatin IF\",\n      \"pmids\": [\"28689661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HAT partner at DSB sites not identified\", \"Quantitative contribution of local vs bulk acetyl-CoA unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined ACLY enzymatic regulation by lipid second messengers and tyrosine phosphorylation, and identified ERAD-mediated proteostatic control of its abundance.\",\n      \"evidence\": \"PIP-binding domain mapping and Lyn kinase assays in AML; Co-IP/MS identification of Hrd1 with in vivo functional rescue\",\n      \"pmids\": [\"32420483\", \"32888949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PIP2/PIP3 binding effect on activity from single lab\", \"Structural basis of tyrosine-phosphorylation-driven activation not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized nuclear ACLY's role across cell types, demonstrating GCN5/KAT2B as the cooperating HAT and identifying deacetylase control of nuclear ACLY pools.\",\n      \"evidence\": \"RANKL differentiation with ACLY-GCN5 epistasis and ChIP in osteoclasts; SIRT6 inactivation with nuclear ACLY quantification; STAT3 promoter binding in endometrial cancer\",\n      \"pmids\": [\"34155695\", \"34573442\", \"33991616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ACLY nuclear import not defined\", \"How SIRT6 controls nuclear ACLY levels mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped a network of acetylation-dependent stability control, where acetylation protects ACLY from ubiquitin ligase recruitment and deacetylation destabilizes it, plus selective autophagic turnover.\",\n      \"evidence\": \"Acetylation-site mutagenesis with NEDD4 interaction (ARHGEF3); SIRT2 deacetylation rescue; K63-ubiquitin/SQSTM1 autophagy assays in granulosa cells\",\n      \"pmids\": [\"36241648\", \"38426936\", \"35404187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-talk between acetylation, K48 and K63 ubiquitination on the same residues not integrated\", \"Most interactions from single labs without reciprocal validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ACLY regulation to ER-stress and metabolic signaling inputs and reinforced the functional distinction between nuclear and cytosolic ACLY in tissue protection.\",\n      \"evidence\": \"Hepatocyte-specific ACLY KO with CUT&RUN (IR injury); SEC63/IRE1\\u03b1 stabilization assays; ENDOG-mTORC2-AKT axis; FBXW7 degradation; ACLY-BP micropeptide protection\",\n      \"pmids\": [\"37983829\", \"37122003\", \"37794041\", \"39781455\", \"37409966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals determining nuclear vs cytosolic partitioning in different tissues not unified\", \"Several upstream regulators characterized in single contexts\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated ACLY couples metabolism to chromatin accessibility and immunity, revealed isoform- and lactylation-based activity control, and uncovered immunogenic consequences of ACLY inhibition.\",\n      \"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\",\n      \"pmids\": [\"39150482\", \"39251781\", \"38055816\", \"40047081\", \"33325591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of lactylation from single lab\", \"Determinants of compensatory ACSS2 engagement across tissues not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural validation of inhibitor binding and connected the SLC25A1-ACLY axis to ferroptosis suppression and anti-tumor immunity, while linking ACLY to neurodegeneration.\",\n      \"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\",\n      \"pmids\": [\"40739358\", \"39881208\", \"40262613\", \"40225566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear ACLY contributes to FSP1 regulation unaddressed\", \"Tissue-specificity of immune consequences across tumor types not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [15, 34]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [15, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 17, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 19, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15, 17, 33, 34]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 17, 18, 35]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GCN5/KAT2B\", \"CTNNB1\", \"NEDD4\", \"FBXW7\", \"SQSTM1\", \"SEC63\", \"ARHGEF3\", \"SLC25A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}