{"gene":"ACSS3","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":2017,"finding":"ACSS3 (rat ortholog) was demonstrated by molecular cloning and recombinant protein expression to be a propionyl-CoA synthetase localized to the mitochondrial matrix, preferentially utilizing propionate as a substrate with a KM of 0.19 mM. Knockdown of acss3 in HepG2 cells significantly decreased propionyl-CoA synthetase activity in cell lysates, and ACSS3 levels/activity were upregulated in liver mitochondria during fasting.","method":"Molecular cloning, recombinant protein purification from E. coli, in vitro enzymatic assay with substrate specificity profiling, subcellular fractionation of liver tissue, siRNA knockdown with enzymatic activity readout","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, KM determination, subcellular fractionation localization, and knockdown functional validation; multiple orthogonal methods in a single study","pmids":["28003429"],"is_preprint":false},{"year":2022,"finding":"ACSS3 is the key enzyme for propionate catabolism in brown adipose tissue, located on the mitochondrial inner membrane. Knockout of Acss3 in mice reduces brown adipose tissue (BAT) mass, increases white adipose tissue (WAT) mass, leads to glucose intolerance and insulin resistance exacerbated by high-fat diet, and elevates propionate levels in BAT and serum. Elevated propionate drives adipocyte autophagy, and pharmacological inhibition of autophagy with hydroxychloroquine ameliorates obesity and insulin resistance in Acss3-/- mice.","method":"Acss3 knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), propionate measurement in BAT and serum, pharmacological autophagy inhibition with hydroxychloroquine, cultured brown/white adipocyte propionate treatment with autophagy readout","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined metabolic phenotype, metabolite measurement, pharmacological rescue experiment; multiple orthogonal methods establishing pathway position","pmids":["35184387"],"is_preprint":false},{"year":2024,"finding":"RPN11 deubiquitinates and stabilizes METTL3, which enhances m6A modification and expression of ACSS3. ACSS3 in turn generates propionyl-CoA that upregulates lipid metabolism genes via histone propionylation. This RPN11-METTL3-ACSS3-histone propionylation pathway is activated in livers of NAFLD patients, and hepatocyte-specific RPN11 knockout protects mice from diet-induced liver steatosis.","method":"Hepatocyte-specific RPN11 knockout mice, diet-induced NAFLD model, mechanistic epistasis linking RPN11-METTL3-ACSS3, histone propionylation assay, human NAFLD liver samples","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with defined phenotype, epistasis established across multiple pathway components, histone propionylation biochemical readout, human tissue validation","pmids":["39146936"],"is_preprint":false},{"year":2021,"finding":"ACSS3 represses prostate cancer progression by reducing lipid droplet (LD) deposits through regulating the stability of the LD coat protein perilipin 3 (PLIN3). Restoration of ACSS3 expression in PCa cells reduces LD deposits, promotes apoptosis by increasing endoplasmic reticulum (ER) stress, decreases de novo intratumoral androgen synthesis, and reverses enzalutamide resistance. Loss of ACSS3 expression in PCa is associated with gene promoter methylation.","method":"Co-IP, qRT-PCR, Western blotting, LC/MS lipid profiling, Oil Red O assay, TG and cholesterol measurement, Bisulfite genomic sequencing PCR and MSP for promoter methylation, CCK-8 and Transwell functional assays, xenograft tumorigenesis model in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for PLIN3 interaction, multiple functional assays, in vivo xenograft validation; single lab but multiple orthogonal methods","pmids":["33391508"],"is_preprint":false},{"year":2023,"finding":"ACSS3 participates in lipid and carbohydrate metabolic homeostasis in alveolar epithelial cells: overexpression downregulates CPT-1A (reducing fatty acid oxidation) and leads to lipid droplet accumulation, while enhancing glycolysis and extracellular lactic acid. ACSS3 increases succinyl-CoA production through propionic acid metabolism and decreases acetyl-CoA and ATP generation. Overexpression of Acss3 in vivo inhibited ECM deposition and attenuated ground-glass opacity in bleomycin-induced pulmonary fibrosis.","method":"Proteomic analysis of IPF patient and bleomycin-mouse samples, ACSS3 overexpression in A549 cells with metabolite measurements (succinyl-CoA, acetyl-CoA, ATP, lactic acid), CPT-1A protein measurement, lipid droplet staining, in vivo bleomycin fibrosis model with micro-CT","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple metabolic readouts and in vivo rescue; single lab, multiple orthogonal methods","pmids":["37979225"],"is_preprint":false},{"year":2020,"finding":"ACSS3 is responsible for lipogenic acetyl-CoA synthesis from acetate in bladder urothelial carcinoma (BLCA) cells under metabolic stress, is required for acetate utilization and histone acetylation, and promotes BLCA cell growth.","method":"Isotope tracing for lipogenic acetyl-CoA generation, ACSS3 knockdown with acetate utilization and histone acetylation readouts, cell growth assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isotope tracing with knockdown and multiple functional readouts (histone acetylation, lipogenic AcCoA, cell growth); single lab","pmids":["32398651"],"is_preprint":false},{"year":2025,"finding":"ACSS3 knockdown in NSCLC cells promotes ferroptosis through transcriptional activation of the p53 pathway, which suppresses the SLC7A11/GPX4 axis. ACSS3 loss enhances p53 stability, and ACSS3 promotes tumor growth by inhibiting p53-mediated ferroptosis. ACSS3 knockdown led to mitochondrial contraction, increased ROS, and decreased mitochondrial membrane potential in NSCLC cells.","method":"ACSS3 knockdown and overexpression in NSCLC cells, in vitro and in vivo tumor growth assays, ferroptosis markers (SLC7A11, GPX4, ROS), p53 stability assessment, mitochondrial morphology/function measurements","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with mechanistic pathway placement (p53-SLC7A11/GPX4 axis), in vivo validation; single lab","pmids":["39961466"],"is_preprint":false},{"year":2025,"finding":"BCL11A transcriptionally represses ACSS3 as a direct target gene. BCL11A deficiency increases ACSS3 expression, promoting autophagosome formation and enhanced autophagy flux, which reduces DNA damage and ROS under UVB irradiation, protecting epidermal cells from UVB-induced death. This protective effect was blocked by pharmacological inhibition of autophagy or BCL11A overexpression.","method":"CRISPR/Cas9-mediated BCL11A deletion, ACSS3 identified as direct transcriptional target, autophagy flux assays, ROS measurement, DNA damage assays, pharmacological autophagy inhibition rescue","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with direct transcriptional target identification and mechanistic rescue experiments; single lab, multiple orthogonal methods","pmids":["41039024"],"is_preprint":false},{"year":2025,"finding":"ACSS3 modulates aerobic glycolysis and keloid fibroblast (KF) activity via the Wnt/β-Catenin pathway. Lentiviral overexpression of ACSS3 in KFs suppressed their activity, normalized glycolytic flux, and reduced levels of critical glycolytic enzymes, while ACSS3 knockdown had opposite effects that were reversed by the Wnt/β-Catenin inhibitor ICG-001.","method":"Lentiviral ACSS3 overexpression and knockdown in keloid fibroblasts, glycolytic flux measurement, glycolytic enzyme levels, pharmacological rescue with ICG-001 (Wnt/β-Catenin inhibitor), single-cell analysis","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on pharmacological inhibitor rescue without direct biochemical demonstration of Wnt/β-Catenin interaction","pmids":["40783148"],"is_preprint":false},{"year":2023,"finding":"The EGFR/AKT pathway upregulates ACSS3 expression in glioblastoma (GBM) cells in an NF-κB-dependent manner, contributing to lipid remodeling and energy metabolism reprogramming in EGFR-activated GBM.","method":"Single-cell RNA sequencing and untargeted metabolomics of clinical GBM, EGFR/AKT pathway inhibition with MK-2206, NF-κB-dependent regulation of ACSS3 expression assessed in GBM cells, intracranial tumor model in vivo","journal":"Cancer communications (London, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from inhibitor experiments; NF-κB dependence not directly validated by mutagenesis or ChIP; single lab","pmids":["37920878"],"is_preprint":false},{"year":2024,"finding":"ACSS3 functions as an acetyltransferase (or donor for acetyltransferase activity) contributing to CBP/p300-mediated acetylation of Sox2 at K75 in colorectal cancer cells, as identified by LC-MS-based proteomics binding partner analysis.","method":"LC-MS-based proteomics to identify binding partners of Sox2 in CRC cell lines, identification of ACSS3 as involved in K75 acetylation of Sox2 along with CBP/p300","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ACSS3 identified as binding partner by proteomics with functional implication for Sox2 K75 acetylation, but mechanistic role of ACSS3 in the acetyltransferase reaction is not directly validated by mutagenesis or reconstitution in this abstract","pmids":["38473392"],"is_preprint":false}],"current_model":"ACSS3 is a mitochondrial matrix/inner membrane acyl-CoA synthetase that preferentially activates propionate to propionyl-CoA (KM ~0.19 mM), thereby serving as the primary enzyme for propionate catabolism in tissues such as liver and brown adipose tissue; loss of ACSS3 causes propionate accumulation that triggers adipocyte autophagy, obesity, and insulin resistance, while the propionyl-CoA it generates also drives histone propionylation to regulate lipid metabolism gene expression downstream of a RPN11-METTL3 axis; additionally, ACSS3 generates lipogenic acetyl-CoA from acetate under metabolic stress, modulates lipid droplet dynamics via PLIN3 stability, influences p53-mediated ferroptosis through the SLC7A11/GPX4 axis, and is transcriptionally repressed by BCL11A, with its expression regulated by NF-κB downstream of EGFR/AKT signaling."},"narrative":{"mechanistic_narrative":"ACSS3 is a mitochondrial acyl-CoA synthetase that serves as the primary enzyme of propionate catabolism, activating propionate to propionyl-CoA in tissues such as liver and brown adipose tissue [PMID:28003429, PMID:35184387]. Biochemical reconstitution with purified recombinant protein established it as a propionyl-CoA synthetase of the mitochondrial matrix that preferentially uses propionate (KM ~0.19 mM) and is induced in liver mitochondria during fasting [PMID:28003429]. In brown adipose tissue ACSS3 resides on the inner mitochondrial membrane, and its loss in mice causes propionate accumulation in BAT and serum that drives adipocyte autophagy, producing obesity, glucose intolerance, and insulin resistance — phenotypes reversed by pharmacological autophagy inhibition [PMID:35184387]. Beyond catabolic clearance, the propionyl-CoA ACSS3 generates feeds histone propionylation that upregulates lipid metabolism genes; this output operates downstream of an RPN11–METTL3 axis in which m6A-dependent ACSS3 induction promotes hepatic steatosis [PMID:39146936]. ACSS3 additionally shapes lipid storage and tumor metabolism: it restrains lipid droplet deposition through stabilization of the coat protein PLIN3 in prostate cancer [PMID:33391508], supports lipogenic acetyl-CoA synthesis from acetate and histone acetylation under metabolic stress in bladder carcinoma [PMID:32398651], and limits p53-mediated ferroptosis via the SLC7A11/GPX4 axis in lung cancer [PMID:39961466]. Its expression is directly repressed by the transcription factor BCL11A, linking ACSS3 to autophagy-dependent protection of epidermal cells from UVB damage [PMID:41039024].","teleology":[{"year":2017,"claim":"Established the core enzymatic identity of ACSS3 — whether it was a bona fide acyl-CoA synthetase and what substrate it acts on — by direct biochemical reconstitution.","evidence":"Recombinant protein purification and in vitro enzymatic assay with substrate specificity profiling, subcellular fractionation, and siRNA knockdown in HepG2 cells","pmids":["28003429"],"confidence":"High","gaps":["Tissue-wide contribution to whole-body propionate flux not assessed in vivo","Structural basis of propionate preference not determined"]},{"year":2022,"claim":"Placed ACSS3 at a defined physiological node by showing that its loss elevates propionate and drives adipocyte autophagy, connecting an enzymatic defect to systemic metabolic disease.","evidence":"Acss3 knockout mouse with metabolic phenotyping, tissue/serum propionate measurement, and pharmacological autophagy-inhibition rescue","pmids":["35184387"],"confidence":"High","gaps":["Molecular mechanism by which propionate triggers autophagy not defined","Whether inner-membrane vs matrix localization reflects tissue-specific differences unresolved"]},{"year":2024,"claim":"Showed that ACSS3-derived propionyl-CoA acts as a signaling input to chromatin, linking its catabolic output to transcriptional control of lipid metabolism via histone propionylation downstream of RPN11-METTL3.","evidence":"Hepatocyte-specific RPN11 knockout mice, diet-induced NAFLD model, epistasis across RPN11-METTL3-ACSS3, histone propionylation assay, human NAFLD tissue","pmids":["39146936"],"confidence":"High","gaps":["Which histone residues are propionylated and which genes they directly control not fully mapped","Direct enzymatic link between ACSS3 and the histone propionylation machinery not reconstituted"]},{"year":2021,"claim":"Extended ACSS3 function to lipid droplet regulation, showing it limits lipid storage and tumor progression through stabilizing the droplet coat protein PLIN3.","evidence":"Co-IP, lipid profiling, promoter methylation analysis, and xenograft assays in prostate cancer cells","pmids":["33391508"],"confidence":"Medium","gaps":["Mechanism by which ACSS3 stabilizes PLIN3 not defined","Single-lab Co-IP without reciprocal validation"]},{"year":2020,"claim":"Demonstrated a second catalytic capacity — generation of lipogenic acetyl-CoA from acetate under metabolic stress feeding histone acetylation — broadening ACSS3 beyond propionate.","evidence":"Isotope tracing, knockdown with acetate utilization and histone acetylation readouts in bladder carcinoma cells","pmids":["32398651"],"confidence":"Medium","gaps":["Relative in vitro efficiency on acetate vs propionate not quantified against [#0]","Single lineage tested"]},{"year":2025,"claim":"Connected ACSS3 to redox/cell-death control, showing its loss enhances p53 stability and ferroptosis via suppression of the SLC7A11/GPX4 axis.","evidence":"Loss- and gain-of-function in NSCLC cells with ferroptosis markers, p53 stability, mitochondrial function readouts, and in vivo tumor growth","pmids":["39961466"],"confidence":"Medium","gaps":["Mechanism coupling ACSS3 enzymatic activity to p53 stabilization unclear","Whether effect requires catalytic function not tested"]},{"year":2025,"claim":"Identified an upstream transcriptional repressor, placing ACSS3 as a direct BCL11A target that mediates autophagy-dependent protection of epidermal cells from UVB damage.","evidence":"CRISPR/Cas9 BCL11A deletion, direct transcriptional target identification, autophagy/ROS/DNA-damage assays with pharmacological rescue","pmids":["41039024"],"confidence":"Medium","gaps":["Direct BCL11A binding to the ACSS3 promoter not shown by ChIP in this entry","How elevated ACSS3 promotes autophagosome formation mechanistically unresolved"]},{"year":2023,"claim":"Implicated ACSS3 in fibrosis-associated metabolic homeostasis, with overexpression reprogramming lipid/carbohydrate flux and attenuating pulmonary fibrosis.","evidence":"Proteomics of IPF/bleomycin samples, ACSS3 overexpression in A549 cells with metabolite measurements, in vivo bleomycin model","pmids":["37979225"],"confidence":"Medium","gaps":["Causal enzymatic basis for the metabolic shifts not isolated","Single-lab overexpression model"]},{"year":null,"claim":"How ACSS3's dual substrate usage (propionate vs acetate) is partitioned across tissues and metabolic states, and whether its diverse downstream phenotypes (autophagy, ferroptosis, lipid droplets) all flow from its acyl-CoA synthetase activity, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model relating substrate preference to context","Catalytic-dead mutant rescue not used to test whether non-metabolic phenotypes require enzyme activity","Reported Wnt/β-Catenin and Sox2 acetyltransferase roles rest on Low-confidence inhibitor/proteomics evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,5]}],"complexes":[],"partners":["PLIN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6R3","full_name":"Acyl-CoA synthetase short-chain family member 3, mitochondrial","aliases":["Acetate--CoA ligase 3","Acyl-CoA synthetase short-chain family member 3","Propionate--CoA ligase"],"length_aa":686,"mass_kda":74.8,"function":"Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:28003429). Propionate is the preferred substrate (PubMed:28003429). Can utilize acetate and butyrate with a much lower affinity (By similarity)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9H6R3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACSS3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACSS3","total_profiled":1310},"omim":[{"mim_id":"614356","title":"ACYL-CoA SYNTHETASE SHORT CHAIN FAMILY, MEMBER 3; ACSS3","url":"https://www.omim.org/entry/614356"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":37.4}],"url":"https://www.proteinatlas.org/search/ACSS3"},"hgnc":{"alias_symbol":["FLJ21963"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6R3","domains":[{"cath_id":"3.30.300.30","chopping":"565-686","consensus_level":"high","plddt":85.1425,"start":565,"end":686}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6R3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6R3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6R3-F1-predicted_aligned_error_v6.png","plddt_mean":86.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACSS3","jax_strain_url":"https://www.jax.org/strain/search?query=ACSS3"},"sequence":{"accession":"Q9H6R3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6R3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6R3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6R3"}},"corpus_meta":[{"pmid":"30482855","id":"PMC_30482855","title":"Metabolic 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molecular cloning and recombinant protein expression to be a propionyl-CoA synthetase localized to the mitochondrial matrix, preferentially utilizing propionate as a substrate with a KM of 0.19 mM. Knockdown of acss3 in HepG2 cells significantly decreased propionyl-CoA synthetase activity in cell lysates, and ACSS3 levels/activity were upregulated in liver mitochondria during fasting.\",\n      \"method\": \"Molecular cloning, recombinant protein purification from E. coli, in vitro enzymatic assay with substrate specificity profiling, subcellular fractionation of liver tissue, siRNA knockdown with enzymatic activity readout\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, KM determination, subcellular fractionation localization, and knockdown functional validation; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"28003429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACSS3 is the key enzyme for propionate catabolism in brown adipose tissue, located on the mitochondrial inner membrane. Knockout of Acss3 in mice reduces brown adipose tissue (BAT) mass, increases white adipose tissue (WAT) mass, leads to glucose intolerance and insulin resistance exacerbated by high-fat diet, and elevates propionate levels in BAT and serum. Elevated propionate drives adipocyte autophagy, and pharmacological inhibition of autophagy with hydroxychloroquine ameliorates obesity and insulin resistance in Acss3-/- mice.\",\n      \"method\": \"Acss3 knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), propionate measurement in BAT and serum, pharmacological autophagy inhibition with hydroxychloroquine, cultured brown/white adipocyte propionate treatment with autophagy readout\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined metabolic phenotype, metabolite measurement, pharmacological rescue experiment; multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"35184387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPN11 deubiquitinates and stabilizes METTL3, which enhances m6A modification and expression of ACSS3. ACSS3 in turn generates propionyl-CoA that upregulates lipid metabolism genes via histone propionylation. This RPN11-METTL3-ACSS3-histone propionylation pathway is activated in livers of NAFLD patients, and hepatocyte-specific RPN11 knockout protects mice from diet-induced liver steatosis.\",\n      \"method\": \"Hepatocyte-specific RPN11 knockout mice, diet-induced NAFLD model, mechanistic epistasis linking RPN11-METTL3-ACSS3, histone propionylation assay, human NAFLD liver samples\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with defined phenotype, epistasis established across multiple pathway components, histone propionylation biochemical readout, human tissue validation\",\n      \"pmids\": [\"39146936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSS3 represses prostate cancer progression by reducing lipid droplet (LD) deposits through regulating the stability of the LD coat protein perilipin 3 (PLIN3). Restoration of ACSS3 expression in PCa cells reduces LD deposits, promotes apoptosis by increasing endoplasmic reticulum (ER) stress, decreases de novo intratumoral androgen synthesis, and reverses enzalutamide resistance. Loss of ACSS3 expression in PCa is associated with gene promoter methylation.\",\n      \"method\": \"Co-IP, qRT-PCR, Western blotting, LC/MS lipid profiling, Oil Red O assay, TG and cholesterol measurement, Bisulfite genomic sequencing PCR and MSP for promoter methylation, CCK-8 and Transwell functional assays, xenograft tumorigenesis model in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for PLIN3 interaction, multiple functional assays, in vivo xenograft validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33391508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSS3 participates in lipid and carbohydrate metabolic homeostasis in alveolar epithelial cells: overexpression downregulates CPT-1A (reducing fatty acid oxidation) and leads to lipid droplet accumulation, while enhancing glycolysis and extracellular lactic acid. ACSS3 increases succinyl-CoA production through propionic acid metabolism and decreases acetyl-CoA and ATP generation. Overexpression of Acss3 in vivo inhibited ECM deposition and attenuated ground-glass opacity in bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"Proteomic analysis of IPF patient and bleomycin-mouse samples, ACSS3 overexpression in A549 cells with metabolite measurements (succinyl-CoA, acetyl-CoA, ATP, lactic acid), CPT-1A protein measurement, lipid droplet staining, in vivo bleomycin fibrosis model with micro-CT\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple metabolic readouts and in vivo rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37979225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACSS3 is responsible for lipogenic acetyl-CoA synthesis from acetate in bladder urothelial carcinoma (BLCA) cells under metabolic stress, is required for acetate utilization and histone acetylation, and promotes BLCA cell growth.\",\n      \"method\": \"Isotope tracing for lipogenic acetyl-CoA generation, ACSS3 knockdown with acetate utilization and histone acetylation readouts, cell growth assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isotope tracing with knockdown and multiple functional readouts (histone acetylation, lipogenic AcCoA, cell growth); single lab\",\n      \"pmids\": [\"32398651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS3 knockdown in NSCLC cells promotes ferroptosis through transcriptional activation of the p53 pathway, which suppresses the SLC7A11/GPX4 axis. ACSS3 loss enhances p53 stability, and ACSS3 promotes tumor growth by inhibiting p53-mediated ferroptosis. ACSS3 knockdown led to mitochondrial contraction, increased ROS, and decreased mitochondrial membrane potential in NSCLC cells.\",\n      \"method\": \"ACSS3 knockdown and overexpression in NSCLC cells, in vitro and in vivo tumor growth assays, ferroptosis markers (SLC7A11, GPX4, ROS), p53 stability assessment, mitochondrial morphology/function measurements\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with mechanistic pathway placement (p53-SLC7A11/GPX4 axis), in vivo validation; single lab\",\n      \"pmids\": [\"39961466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BCL11A transcriptionally represses ACSS3 as a direct target gene. BCL11A deficiency increases ACSS3 expression, promoting autophagosome formation and enhanced autophagy flux, which reduces DNA damage and ROS under UVB irradiation, protecting epidermal cells from UVB-induced death. This protective effect was blocked by pharmacological inhibition of autophagy or BCL11A overexpression.\",\n      \"method\": \"CRISPR/Cas9-mediated BCL11A deletion, ACSS3 identified as direct transcriptional target, autophagy flux assays, ROS measurement, DNA damage assays, pharmacological autophagy inhibition rescue\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with direct transcriptional target identification and mechanistic rescue experiments; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41039024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS3 modulates aerobic glycolysis and keloid fibroblast (KF) activity via the Wnt/β-Catenin pathway. Lentiviral overexpression of ACSS3 in KFs suppressed their activity, normalized glycolytic flux, and reduced levels of critical glycolytic enzymes, while ACSS3 knockdown had opposite effects that were reversed by the Wnt/β-Catenin inhibitor ICG-001.\",\n      \"method\": \"Lentiviral ACSS3 overexpression and knockdown in keloid fibroblasts, glycolytic flux measurement, glycolytic enzyme levels, pharmacological rescue with ICG-001 (Wnt/β-Catenin inhibitor), single-cell analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on pharmacological inhibitor rescue without direct biochemical demonstration of Wnt/β-Catenin interaction\",\n      \"pmids\": [\"40783148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The EGFR/AKT pathway upregulates ACSS3 expression in glioblastoma (GBM) cells in an NF-κB-dependent manner, contributing to lipid remodeling and energy metabolism reprogramming in EGFR-activated GBM.\",\n      \"method\": \"Single-cell RNA sequencing and untargeted metabolomics of clinical GBM, EGFR/AKT pathway inhibition with MK-2206, NF-κB-dependent regulation of ACSS3 expression assessed in GBM cells, intracranial tumor model in vivo\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from inhibitor experiments; NF-κB dependence not directly validated by mutagenesis or ChIP; single lab\",\n      \"pmids\": [\"37920878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS3 functions as an acetyltransferase (or donor for acetyltransferase activity) contributing to CBP/p300-mediated acetylation of Sox2 at K75 in colorectal cancer cells, as identified by LC-MS-based proteomics binding partner analysis.\",\n      \"method\": \"LC-MS-based proteomics to identify binding partners of Sox2 in CRC cell lines, identification of ACSS3 as involved in K75 acetylation of Sox2 along with CBP/p300\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ACSS3 identified as binding partner by proteomics with functional implication for Sox2 K75 acetylation, but mechanistic role of ACSS3 in the acetyltransferase reaction is not directly validated by mutagenesis or reconstitution in this abstract\",\n      \"pmids\": [\"38473392\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSS3 is a mitochondrial matrix/inner membrane acyl-CoA synthetase that preferentially activates propionate to propionyl-CoA (KM ~0.19 mM), thereby serving as the primary enzyme for propionate catabolism in tissues such as liver and brown adipose tissue; loss of ACSS3 causes propionate accumulation that triggers adipocyte autophagy, obesity, and insulin resistance, while the propionyl-CoA it generates also drives histone propionylation to regulate lipid metabolism gene expression downstream of a RPN11-METTL3 axis; additionally, ACSS3 generates lipogenic acetyl-CoA from acetate under metabolic stress, modulates lipid droplet dynamics via PLIN3 stability, influences p53-mediated ferroptosis through the SLC7A11/GPX4 axis, and is transcriptionally repressed by BCL11A, with its expression regulated by NF-κB downstream of EGFR/AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACSS3 is a mitochondrial acyl-CoA synthetase that serves as the primary enzyme of propionate catabolism, activating propionate to propionyl-CoA in tissues such as liver and brown adipose tissue [#0, #1]. Biochemical reconstitution with purified recombinant protein established it as a propionyl-CoA synthetase of the mitochondrial matrix that preferentially uses propionate (KM ~0.19 mM) and is induced in liver mitochondria during fasting [#0]. In brown adipose tissue ACSS3 resides on the inner mitochondrial membrane, and its loss in mice causes propionate accumulation in BAT and serum that drives adipocyte autophagy, producing obesity, glucose intolerance, and insulin resistance — phenotypes reversed by pharmacological autophagy inhibition [#1]. Beyond catabolic clearance, the propionyl-CoA ACSS3 generates feeds histone propionylation that upregulates lipid metabolism genes; this output operates downstream of an RPN11–METTL3 axis in which m6A-dependent ACSS3 induction promotes hepatic steatosis [#2]. ACSS3 additionally shapes lipid storage and tumor metabolism: it restrains lipid droplet deposition through stabilization of the coat protein PLIN3 in prostate cancer [#3], supports lipogenic acetyl-CoA synthesis from acetate and histone acetylation under metabolic stress in bladder carcinoma [#5], and limits p53-mediated ferroptosis via the SLC7A11/GPX4 axis in lung cancer [#6]. Its expression is directly repressed by the transcription factor BCL11A, linking ACSS3 to autophagy-dependent protection of epidermal cells from UVB damage [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the core enzymatic identity of ACSS3 — whether it was a bona fide acyl-CoA synthetase and what substrate it acts on — by direct biochemical reconstitution.\",\n      \"evidence\": \"Recombinant protein purification and in vitro enzymatic assay with substrate specificity profiling, subcellular fractionation, and siRNA knockdown in HepG2 cells\",\n      \"pmids\": [\"28003429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-wide contribution to whole-body propionate flux not assessed in vivo\", \"Structural basis of propionate preference not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed ACSS3 at a defined physiological node by showing that its loss elevates propionate and drives adipocyte autophagy, connecting an enzymatic defect to systemic metabolic disease.\",\n      \"evidence\": \"Acss3 knockout mouse with metabolic phenotyping, tissue/serum propionate measurement, and pharmacological autophagy-inhibition rescue\",\n      \"pmids\": [\"35184387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which propionate triggers autophagy not defined\", \"Whether inner-membrane vs matrix localization reflects tissue-specific differences unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that ACSS3-derived propionyl-CoA acts as a signaling input to chromatin, linking its catabolic output to transcriptional control of lipid metabolism via histone propionylation downstream of RPN11-METTL3.\",\n      \"evidence\": \"Hepatocyte-specific RPN11 knockout mice, diet-induced NAFLD model, epistasis across RPN11-METTL3-ACSS3, histone propionylation assay, human NAFLD tissue\",\n      \"pmids\": [\"39146936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which histone residues are propionylated and which genes they directly control not fully mapped\", \"Direct enzymatic link between ACSS3 and the histone propionylation machinery not reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ACSS3 function to lipid droplet regulation, showing it limits lipid storage and tumor progression through stabilizing the droplet coat protein PLIN3.\",\n      \"evidence\": \"Co-IP, lipid profiling, promoter methylation analysis, and xenograft assays in prostate cancer cells\",\n      \"pmids\": [\"33391508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ACSS3 stabilizes PLIN3 not defined\", \"Single-lab Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a second catalytic capacity — generation of lipogenic acetyl-CoA from acetate under metabolic stress feeding histone acetylation — broadening ACSS3 beyond propionate.\",\n      \"evidence\": \"Isotope tracing, knockdown with acetate utilization and histone acetylation readouts in bladder carcinoma cells\",\n      \"pmids\": [\"32398651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative in vitro efficiency on acetate vs propionate not quantified against [#0]\", \"Single lineage tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ACSS3 to redox/cell-death control, showing its loss enhances p53 stability and ferroptosis via suppression of the SLC7A11/GPX4 axis.\",\n      \"evidence\": \"Loss- and gain-of-function in NSCLC cells with ferroptosis markers, p53 stability, mitochondrial function readouts, and in vivo tumor growth\",\n      \"pmids\": [\"39961466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling ACSS3 enzymatic activity to p53 stabilization unclear\", \"Whether effect requires catalytic function not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream transcriptional repressor, placing ACSS3 as a direct BCL11A target that mediates autophagy-dependent protection of epidermal cells from UVB damage.\",\n      \"evidence\": \"CRISPR/Cas9 BCL11A deletion, direct transcriptional target identification, autophagy/ROS/DNA-damage assays with pharmacological rescue\",\n      \"pmids\": [\"41039024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BCL11A binding to the ACSS3 promoter not shown by ChIP in this entry\", \"How elevated ACSS3 promotes autophagosome formation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated ACSS3 in fibrosis-associated metabolic homeostasis, with overexpression reprogramming lipid/carbohydrate flux and attenuating pulmonary fibrosis.\",\n      \"evidence\": \"Proteomics of IPF/bleomycin samples, ACSS3 overexpression in A549 cells with metabolite measurements, in vivo bleomycin model\",\n      \"pmids\": [\"37979225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal enzymatic basis for the metabolic shifts not isolated\", \"Single-lab overexpression model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACSS3's dual substrate usage (propionate vs acetate) is partitioned across tissues and metabolic states, and whether its diverse downstream phenotypes (autophagy, ferroptosis, lipid droplets) all flow from its acyl-CoA synthetase activity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model relating substrate preference to context\", \"Catalytic-dead mutant rescue not used to test whether non-metabolic phenotypes require enzyme activity\", \"Reported Wnt/\\u03b2-Catenin and Sox2 acetyltransferase roles rest on Low-confidence inhibitor/proteomics evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLIN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}