{"gene":"ACACA","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2002,"finding":"SREBP-1 directly interacts with the thyroid hormone receptor (TR) on the ACCalpha (ACACA) gene promoter to enhance T3-induced transcription. Treatment with T3 or insulin increases mature SREBP-1 abundance, while cAMP or hexanoate suppresses this increase; inhibition of ACCalpha transcription by cAMP or hexanoate is mediated by sequences between -101 and -71 bp of the ACACA promoter.","method":"Transfection/reporter assays, time-course studies of SREBP-1 protein abundance in hepatocytes, pharmacological treatments (T3, insulin, cAMP, hexanoate)","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transfection, protein abundance measurement, defined cis-element), single lab","pmids":["12576518"],"is_preprint":false},{"year":2005,"finding":"The 5' end of ACACA is located within a CpG island that harbors a bidirectional promoter shared with the divergently oriented TADA2L gene; RNA polymerase II concentration within the intergenic region reflects tissue-specific abundance of both transcripts, but regulation of Pol II clearance from the promoter and elongation rate appear to be determinants of the asymmetric expression of ACACA and TADA2L transcripts.","method":"5' boundary delineation across four species, RNA Pol II ChIP in mouse brain vs. liver, transcript quantification","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for Pol II occupancy combined with cross-species sequence analysis and transcript quantification, single lab","pmids":["15607423"],"is_preprint":false},{"year":2018,"finding":"ACACA (and ACACB) are direct binding targets of the environmental pollutant PFOA, identified by cysteine-reactive chemical proteomics probes; binding was verified by thermal shift assay and targeted proteomics (PRM), providing a mechanistic explanation for PFOA-induced abnormal fatty acid metabolism.","method":"Cysteine-targeting chemical proteomics (IAA and EBX probes), quantitative proteomics, parallel reaction monitoring (PRM), thermal shift assay, targeted metabolomics","journal":"Analytical chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal chemical proteomics and biophysical validation methods (chemical probe enrichment, PRM, thermal shift assay) in a single rigorous study","pmids":["30134650"],"is_preprint":false},{"year":2021,"finding":"Biallelic loss-of-function mutations in ACACA reduce ACC1 protein level and enzyme activity in patient-derived cells, causing disrupted lipid homeostasis (altered lipidomic profile), impaired cell motility, and a neurodevelopmental syndrome (global developmental delay, microcephaly, hypotonia). Cell motility deficit was recapitulated by RNAi-mediated ACC1 knockdown in fibroblasts and was partially rescued by palmitate supplementation.","method":"Whole-exome sequencing, ACC1 enzyme activity assay in patient lymphocytes, lipidomics, cell proliferation/apoptosis/migration assays, siRNA knockdown, palmitate rescue","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzyme activity measured directly in patient cells, lipidomics, functional rescue with palmitate, and RNAi recapitulation, multiple orthogonal methods in single study","pmids":["34552920"],"is_preprint":false},{"year":2021,"finding":"ACACA knockdown in prostate cancer cells (DU145 and PC3) reduces proliferation, decreases mitochondrial ATP production, lowers mitochondrial DNA levels and MitoTracker staining, and elevates NAD+/NADH ratio and ROS levels, linking ACACA activity to mitochondrial function.","method":"siRNA knockdown, cell cycle and proliferation assays, mito-ATP measurement, mitochondrial staining (MitoTracker), mtDNA quantification, NAD+/NADH and ROS assays, xenograft tumor model","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (metabolic, mitochondrial, in vivo) in a single lab study","pmids":["33391420"],"is_preprint":false},{"year":2023,"finding":"Downregulation of ACACA in lung fibroblasts reduces acetylation of protein lysine residues and fatty acid synthesis, triggers a senescent and inflammatory phenotypic shift (SASP), and enables CXCL1-mediated recruitment of granulocytic myeloid-derived suppressor cells into the lung, thereby promoting formation of an immunosuppressive pre-metastatic niche. ACACA knock-in prevented lung metastasis in the MMTV-PyVT mouse model.","method":"Transcriptomics (microarray), lipidomics (LC-MS/MS), co-culture of lung fibroblasts with breast cancer cells, immunoblot, IHC, qRT-PCR, senescence assays (SA-β-Gal), ACACA knock-in mouse model","journal":"Cellular oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway established with in vivo genetic rescue (knock-in), lipidomics, transcriptomics, and multiple cellular assays; in vivo confirmation with causal readout","pmids":["36607556"],"is_preprint":false},{"year":2024,"finding":"Inhibition of ACACA in a lipid accumulation cell model reduces intracellular TG and TC, alleviates mitochondrial dysfunction (preserving MMP, ATP production, reducing ROS), and enhances fatty acid oxidation via activation of the AMPK–PPARα–CPT1A pathway.","method":"siRNA knockdown, CMS-121 pharmacological inhibitor, lipid quantification, mitochondrial function assays (MMP, ATP, ROS, MRC complex expression), AMPK/PPARα/CPT1A western blotting, high-fat diet mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and cellular readouts with both genetic and pharmacological inhibition in single lab","pmids":["38395901"],"is_preprint":false},{"year":2024,"finding":"IL-17A activates the mTORC2–ACACA signaling pathway in corpus cavernosum smooth muscle cells (CSMCs), upregulating lipid synthesis and senescence transition, leading to increased secretion of fibro-matrix proteins and fibrosis; blockade of this signaling improved erectile function in a neurogenic ED rat model.","method":"PCR array, western blotting, immunofluorescence, IHC, non-target metabolomics, siRNA, SA-β-Gal staining, in vivo rat neurogenic ED model with IL-17A antagonist","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway assignment via siRNA + metabolomics + in vivo pharmacological validation, single lab","pmids":["39256772"],"is_preprint":false},{"year":2024,"finding":"AKR1B10 co-localizes with and regulates ACCα (ACACA) activity in hepatocytes; nicotinate-curcumin inhibits AKR1B10 binding to AKR1B10, reducing ACACA expression and activity, decreasing Malonyl-CoA levels, and thereby suppressing triglyceride and free fatty acid synthesis in NASH.","method":"Molecular docking, western blotting, immunofluorescence co-localization, ELISA (Acetyl-CoA and Malonyl-CoA activity), Ox-LDL-induced HepG2 cell model, rat NASH model","journal":"Lipids in health and disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization and pharmacological inhibition without direct protein-protein interaction validation (e.g., co-IP); molecular docking is computational","pmids":["38937844"],"is_preprint":false},{"year":2025,"finding":"ACACA depletion in androgen receptor-independent prostate cancer cells (via shRNA or TOFA inhibitor) elevates arachidonic acid and eicosanoid levels, increases cPLA2 expression, and activates NF-κB signaling, thereby enhancing cell migration and metastasis. Inhibiting cPLA2 or NF-κB reversed these pro-metastatic effects, placing ACACA upstream of the cPLA2–AA–NF-κB axis.","method":"shRNA knockdown, TOFA pharmacological inhibition, transcriptomics, metabolomics, single-cell RNA sequencing, qPCR, western blotting, immunofluorescence, wound healing and transwell assays, mouse tail vein metastasis model, targeted cPLA2/NF-κB inhibition","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis established via genetic + pharmacological inhibition with multiple orthogonal omics and in vivo validation, single lab","pmids":["40713618"],"is_preprint":false},{"year":2026,"finding":"ZXDB (RNA-binding protein) directly interacts with EIF4A3 via its aa151–300 region and recruits EIF4A3 to the ACACA 5'UTR to enhance ACACA translation; macrophage-specific Zxdb deletion reduces ACACA expression, attenuates pro-inflammatory cytokine secretion and glycolytic reprogramming, and alleviates sepsis-induced acute kidney injury in mice.","method":"Co-IP (ZXDB–EIF4A3 interaction with domain mapping), 5'UTR-dependent translation assay, macrophage-specific Zxdb knockout mouse model, SI-AKI model, qPCR, western blotting","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein–protein interaction with domain mapping, 5'UTR functional assay, and in vivo genetic knockout validation in single lab","pmids":["41873808"],"is_preprint":false},{"year":2026,"finding":"IRX1 transcription factor interacts with NME1 and promotes NME1 nuclear localization; nuclear NME1 then facilitates IRX1-mediated transcriptional downregulation of ACACA, thereby suppressing de novo fatty acid synthesis and breast cancer progression. IRX1 promoter hypermethylation causes its loss in breast cancer.","method":"Co-IP (IRX1–NME1), subcellular fractionation/localization, reporter/ChIP assays for ACACA transcription, in vitro and in vivo (xenograft) tumor growth assays, siRNA/overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP for protein interaction, localization experiment, transcriptional target validation, and in vivo confirmation, single lab","pmids":["42225620"],"is_preprint":false},{"year":2025,"finding":"CRISPRi screening identified ACACA as a key mediator of 1-deoxy-sphingolipid (1-deoxySL)-induced cellular toxicity; genetic knockdown validated that ACACA (involved in very long-chain fatty acid biosynthesis) modulates 1-deoxySL-induced cytotoxicity, mitochondrial toxicity, and neuronal toxicity.","method":"CRISPRi genome-wide screen, genetic knockdown validation, cytotoxicity assays, stable isotope-resolved lipidomics (LC-MS/MS)","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPRi screen hit with knockdown validation but mechanistic follow-up for ACACA specifically is limited; preprint, not peer reviewed","pmids":[],"is_preprint":true}],"current_model":"ACACA (ACC1/ACCα) is the rate-limiting enzyme catalyzing carboxylation of acetyl-CoA to malonyl-CoA, the first committed step in de novo fatty acid synthesis; its transcription is co-regulated by a bidirectional promoter shared with TADA2L and is induced by SREBP-1 acting cooperatively with the thyroid hormone receptor TR, while being suppressed by cAMP and medium-chain fatty acids; its protein is directly bound by PFOA (environmental pollutant) at reactive cysteines; upstream, ZXDB recruits EIF4A3 to the ACACA 5'UTR to enhance its translation, and IRX1-NME1 transcriptionally represses it; downstream, ACACA activity sustains mitochondrial function (ATP production, redox balance) and suppresses the AMPK–PPARα–CPT1A fatty acid oxidation axis, while ACACA depletion in androgen-receptor-independent prostate cancer paradoxically activates the cPLA2–arachidonic acid–NF-κB inflammatory axis to promote metastasis; in non-malignant fibroblasts, ACACA downregulation triggers a senescent/SASP phenotype via reduced protein acetylation and fatty acid synthesis, enabling immunosuppressive pre-metastatic niche formation."},"narrative":{"mechanistic_narrative":"ACACA (ACC1/ACCα) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis, and its activity governs cellular lipid homeostasis, mitochondrial function, and the balance between fatty acid synthesis and oxidation [PMID:34552920, PMID:33391420, PMID:38395901]. Its hepatic transcription is induced through cooperative binding of SREBP-1 and the thyroid hormone receptor at the ACACA promoter, an effect potentiated by T3 and insulin and suppressed by cAMP and medium-chain fatty acids acting through a defined cis-element (-101 to -71 bp) [PMID:12576518]; the gene's 5' end lies in a CpG island containing a bidirectional promoter shared with the divergently transcribed TADA2L gene [PMID:15607423]. ACACA is additionally controlled post-transcriptionally and post-translationally: the RNA-binding protein ZXDB recruits EIF4A3 to the ACACA 5'UTR to enhance its translation [PMID:41873808], the transcription factor IRX1 together with nuclear NME1 represses its transcription [PMID:42225620], and the environmental pollutant PFOA binds ACACA at reactive cysteines [PMID:30134650]. Functionally, ACACA activity sustains mitochondrial ATP production, mtDNA levels, and redox balance while restraining the AMPK–PPARα–CPT1A fatty acid oxidation axis [PMID:33391420, PMID:38395901]; loss of ACACA elsewhere drives pathological phenotypes including a senescent SASP state in fibroblasts that recruits myeloid-derived suppressor cells to seed an immunosuppressive pre-metastatic niche [PMID:36607556] and, in androgen-receptor-independent prostate cancer, activation of the cPLA2–arachidonic acid–NF-κB inflammatory axis that promotes metastasis [PMID:40713618]. Biallelic loss-of-function mutations in ACACA reduce enzyme activity and cause a neurodevelopmental syndrome with global developmental delay, microcephaly, and hypotonia, with a cell-motility defect partially rescued by palmitate [PMID:34552920].","teleology":[{"year":2002,"claim":"Established how hormonal and nutritional signals converge on the ACACA promoter, identifying SREBP-1/TR cooperativity as the activating axis and a discrete cis-element mediating cAMP/medium-chain-fatty-acid repression.","evidence":"Reporter/transfection assays and SREBP-1 protein time-courses in hepatocytes under T3, insulin, cAMP, and hexanoate","pmids":["12576518"],"confidence":"Medium","gaps":["Limited to hepatocytes; tissue generality untested","Does not address post-transcriptional regulation","Endogenous chromatin occupancy of SREBP-1/TR not directly mapped"]},{"year":2005,"claim":"Defined the genomic architecture of ACACA transcription, showing it shares a bidirectional CpG-island promoter with TADA2L and that asymmetric expression is set by Pol II clearance/elongation rather than promoter sequence alone.","evidence":"Cross-species 5' boundary delineation, Pol II ChIP in mouse brain vs. liver, transcript quantification","pmids":["15607423"],"confidence":"Medium","gaps":["Mechanism controlling differential Pol II elongation unresolved","Functional consequence of TADA2L co-regulation for ACACA unclear"]},{"year":2018,"claim":"Showed that ACACA is a direct molecular target of an environmental pollutant, providing a chemical basis for PFOA-induced fatty acid metabolism abnormalities.","evidence":"Cysteine-reactive chemical proteomics with PRM and thermal shift validation","pmids":["30134650"],"confidence":"High","gaps":["Specific reactive cysteine residues and effect on catalytic activity not fully resolved","Physiological relevance of binding stoichiometry untested"]},{"year":2021,"claim":"Linked ACACA loss-of-function to a human Mendelian neurodevelopmental syndrome and demonstrated that its lipid output supports cell motility, establishing a causal genotype-phenotype connection.","evidence":"Whole-exome sequencing, patient-cell enzyme assays, lipidomics, RNAi recapitulation, and palmitate rescue","pmids":["34552920"],"confidence":"High","gaps":["Mechanism connecting reduced fatty acid synthesis to neurodevelopment not defined","How palmitate restores motility molecularly unresolved"]},{"year":2021,"claim":"Connected ACACA activity to mitochondrial bioenergetics and redox state in cancer cells, beyond its canonical biosynthetic role.","evidence":"siRNA knockdown in prostate cancer cells with mito-ATP, mtDNA, MitoTracker, NAD+/NADH, ROS readouts and xenografts","pmids":["33391420"],"confidence":"Medium","gaps":["Causal link between malonyl-CoA output and mtDNA maintenance unclear","Direct vs. indirect effect on mitochondria not separated"]},{"year":2023,"claim":"Revealed a non-cell-autonomous role: ACACA downregulation in fibroblasts induces senescence/SASP via reduced protein acetylation and lipid synthesis, recruiting MDSCs to build an immunosuppressive pre-metastatic niche.","evidence":"Transcriptomics, lipidomics, fibroblast–tumor co-culture, and an ACACA knock-in mouse rescuing lung metastasis","pmids":["36607556"],"confidence":"High","gaps":["Source of acetyl-CoA limitation driving hypoacetylation not pinpointed","Which acetylated targets mediate the SASP unknown"]},{"year":2024,"claim":"Demonstrated reciprocal control of fatty acid oxidation: ACACA inhibition relieves the AMPK–PPARα–CPT1A axis to enhance oxidation and rescue lipid-overload mitochondrial dysfunction.","evidence":"siRNA plus CMS-121 inhibitor in a lipid-accumulation model with mitochondrial and AMPK/PPARα/CPT1A readouts and a high-fat-diet model","pmids":["38395901"],"confidence":"Medium","gaps":["Whether AMPK activation is via malonyl-CoA depletion not directly proven","Tissue specificity of the response untested"]},{"year":2024,"claim":"Placed ACACA downstream of IL-17A/mTORC2 signaling in driving lipid-synthesis-dependent senescence and fibrosis in smooth muscle.","evidence":"PCR array, siRNA, metabolomics, and an in vivo neurogenic ED rat model with IL-17A antagonist","pmids":["39256772"],"confidence":"Medium","gaps":["Direct mechanism linking mTORC2 to ACACA regulation undefined","Generalizability beyond cavernosum smooth muscle unknown"]},{"year":2024,"claim":"Proposed AKR1B10 as a regulator of ACACA activity in hepatocytes relevant to NASH lipogenesis.","evidence":"Molecular docking, immunofluorescence co-localization, and ELISA-based malonyl-CoA assays in cell and rat NASH models","pmids":["38937844"],"confidence":"Low","gaps":["Co-localization and docking without direct co-IP validation of physical interaction","Mechanism by which AKR1B10 modulates ACACA activity unproven"]},{"year":2025,"claim":"Established epistasis placing ACACA upstream of the cPLA2–arachidonic acid–NF-κB axis, explaining how ACACA loss paradoxically promotes prostate cancer metastasis.","evidence":"shRNA/TOFA inhibition with transcriptomics, metabolomics, scRNA-seq, tail-vein metastasis, and rescue by cPLA2/NF-κB blockade","pmids":["40713618"],"confidence":"Medium","gaps":["How reduced malonyl-CoA liberates arachidonic acid for cPLA2 not mechanistically defined","Restricted to AR-independent prostate cancer context"]},{"year":2026,"claim":"Identified post-transcriptional activation of ACACA: ZXDB recruits EIF4A3 to the 5'UTR to boost translation, coupling ACACA to macrophage inflammatory and glycolytic reprogramming.","evidence":"Co-IP with domain mapping, 5'UTR-dependent translation assay, and macrophage-specific Zxdb knockout in a sepsis-AKI model","pmids":["41873808"],"confidence":"Medium","gaps":["Direct binding of ZXDB/EIF4A3 to the ACACA 5'UTR vs. indirect effect not fully separated","Whether translational control operates in non-macrophage cells unknown"]},{"year":2026,"claim":"Defined a transcriptional repression module in which IRX1 and nuclear NME1 downregulate ACACA to restrain de novo lipogenesis and breast cancer progression.","evidence":"Reciprocal co-IP, subcellular fractionation, reporter/ChIP for ACACA, and xenograft assays","pmids":["42225620"],"confidence":"Medium","gaps":["Direct binding of IRX1/NME1 to the ACACA promoter region not finely mapped","Role of NME1 nucleotide-kinase activity in repression unclear"]},{"year":null,"claim":"How the diverse upstream regulators (SREBP-1/TR, ZXDB/EIF4A3, IRX1/NME1, AKR1B10) are integrated to set ACACA output in a given tissue, and how malonyl-CoA depletion mechanistically rewires mitochondrial bioenergetics and eicosanoid signaling, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model integrating transcriptional, translational, and post-translational control","Structural basis of regulator binding and PFOA modification not determined","Causal chain from malonyl-CoA levels to downstream phenotypes incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,6]}],"complexes":[],"partners":["SREBP-1","THRA","AKR1B10","ZXDB","EIF4A3","IRX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13085","full_name":"Acetyl-CoA carboxylase 1","aliases":["Acetyl-Coenzyme A carboxylase alpha","ACC-alpha"],"length_aa":2346,"mass_kda":265.6,"function":"Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis (PubMed:20457939, PubMed:20952656, PubMed:29899443). This is a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:20457939, PubMed:20952656, PubMed:29899443)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q13085/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACACA","classification":"Not Classified","n_dependent_lines":379,"n_total_lines":1208,"dependency_fraction":0.31374172185430466},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACACA","total_profiled":1310},"omim":[{"mim_id":"616279","title":"CATARACT 43; CTRCT43","url":"https://www.omim.org/entry/616279"},{"mim_id":"613933","title":"ACETYL-CoA CARBOXYLASE-ALPHA DEFICIENCY; ACACAD","url":"https://www.omim.org/entry/613933"},{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"},{"mim_id":"609415","title":"MICRO RNA 17 HOST GENE; MIR17HG","url":"https://www.omim.org/entry/609415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACACA"},"hgnc":{"alias_symbol":["ACC1","ACC-alpha","ACCA","ACCalpha","ACACalpha","Acac1","hACC1"],"prev_symbol":["ACAC","ACC"]},"alphafold":{"accession":"Q13085","domains":[{"cath_id":"3.30.1490.20","chopping":"308-352","consensus_level":"medium","plddt":83.5198,"start":308,"end":352},{"cath_id":"3.30.470.20","chopping":"504-625","consensus_level":"medium","plddt":85.303,"start":504,"end":625},{"cath_id":"2.40.50.100","chopping":"754-827","consensus_level":"high","plddt":82.9019,"start":754,"end":827},{"cath_id":"-","chopping":"850-1088","consensus_level":"medium","plddt":86.5092,"start":850,"end":1088},{"cath_id":"3.90.226.10","chopping":"1582-1726_1792-1905","consensus_level":"medium","plddt":90.886,"start":1582,"end":1905},{"cath_id":"2.40.460.10","chopping":"1729-1786","consensus_level":"high","plddt":89.0453,"start":1729,"end":1786},{"cath_id":"3.90.226.10","chopping":"1910-2114_2193-2203","consensus_level":"medium","plddt":93.1143,"start":1910,"end":2203},{"cath_id":"-","chopping":"2121-2191","consensus_level":"high","plddt":89.2363,"start":2121,"end":2191},{"cath_id":"3.30.700","chopping":"628-747","consensus_level":"high","plddt":87.9546,"start":628,"end":747}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13085","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13085-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13085-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACACA","jax_strain_url":"https://www.jax.org/strain/search?query=ACACA"},"sequence":{"accession":"Q13085","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13085.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13085/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13085"}},"corpus_meta":[{"pmid":"26632252","id":"PMC_26632252","title":"MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26632252","citation_count":158,"is_preprint":false},{"pmid":"38395901","id":"PMC_38395901","title":"ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARα- CPT1A axis.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38395901","citation_count":90,"is_preprint":false},{"pmid":"12576518","id":"PMC_12576518","title":"SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACCalpha transcription in hepatocytes.","date":"2002","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/12576518","citation_count":76,"is_preprint":false},{"pmid":"23657179","id":"PMC_23657179","title":"The ACACA and SREBF1 genes are promising markers for pig carcass and performance traits, but not for fatty acid content in the longissimus dorsi muscle and adipose tissue.","date":"2013","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/23657179","citation_count":34,"is_preprint":false},{"pmid":"22718502","id":"PMC_22718502","title":"The SNPs in the ACACA gene are effective on fatty acid composition in Holstein milk.","date":"2012","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/22718502","citation_count":33,"is_preprint":false},{"pmid":"31940936","id":"PMC_31940936","title":"Evaluation of SCD, ACACA and FASN Mutations: Effects on Pork Quality and Other Production Traits in Pigs Selected Based on RNA-Seq Results.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/31940936","citation_count":31,"is_preprint":false},{"pmid":"32236577","id":"PMC_32236577","title":"Circular RNA circ‑ACACA regulates proliferation, migration and glycolysis in non‑small‑cell lung carcinoma via miR‑1183 and PI3K/PKB pathway.","date":"2020","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32236577","citation_count":30,"is_preprint":false},{"pmid":"36607556","id":"PMC_36607556","title":"Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts.","date":"2023","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36607556","citation_count":30,"is_preprint":false},{"pmid":"33391420","id":"PMC_33391420","title":"Down-regulation of ACACA suppresses the malignant progression of Prostate Cancer through inhibiting mitochondrial potential.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33391420","citation_count":25,"is_preprint":false},{"pmid":"15607423","id":"PMC_15607423","title":"Asymmetric expression of transcripts 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Traits of Najdi Sheep.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/37106880","citation_count":1,"is_preprint":false},{"pmid":"41620551","id":"PMC_41620551","title":"ACACA modulates R-loop homeostasis to enhance lipid metabolism and microenvironmental interactions in ccRCC.","date":"2026","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41620551","citation_count":0,"is_preprint":false},{"pmid":"41664674","id":"PMC_41664674","title":"Methylation analysis of PHOSPHO1 and ACACA gene promoters in whole blood samples: insights into metabolic syndrome and associated factors.","date":"2026","source":"Journal of diabetes and metabolic disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41664674","citation_count":0,"is_preprint":false},{"pmid":"41729978","id":"PMC_41729978","title":"Integrated Multiomic Analysis Provides New Insights into the Adipogenic Differentiation of Porcine Adipocytes and Reveals the Regulatory Role of ACACA in Adipogenesis.","date":"2026","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41729978","citation_count":0,"is_preprint":false},{"pmid":"41873808","id":"PMC_41873808","title":"ZXDB Drives Macrophage Inflammatory Programming in Sepsis-Induced Acute Kidney Injury by Recruiting EIF4A3 to Enhance ACACA Translation.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41873808","citation_count":0,"is_preprint":false},{"pmid":"42225620","id":"PMC_42225620","title":"IRX1 suppresses breast cancer progression by inhibiting fatty acid de novo synthesis through downregulating ACACA expression.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42225620","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.18.665488","title":"Coffee consumption affects 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2002,\n      \"finding\": \"SREBP-1 directly interacts with the thyroid hormone receptor (TR) on the ACCalpha (ACACA) gene promoter to enhance T3-induced transcription. Treatment with T3 or insulin increases mature SREBP-1 abundance, while cAMP or hexanoate suppresses this increase; inhibition of ACCalpha transcription by cAMP or hexanoate is mediated by sequences between -101 and -71 bp of the ACACA promoter.\",\n      \"method\": \"Transfection/reporter assays, time-course studies of SREBP-1 protein abundance in hepatocytes, pharmacological treatments (T3, insulin, cAMP, hexanoate)\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transfection, protein abundance measurement, defined cis-element), single lab\",\n      \"pmids\": [\"12576518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The 5' end of ACACA is located within a CpG island that harbors a bidirectional promoter shared with the divergently oriented TADA2L gene; RNA polymerase II concentration within the intergenic region reflects tissue-specific abundance of both transcripts, but regulation of Pol II clearance from the promoter and elongation rate appear to be determinants of the asymmetric expression of ACACA and TADA2L transcripts.\",\n      \"method\": \"5' boundary delineation across four species, RNA Pol II ChIP in mouse brain vs. liver, transcript quantification\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for Pol II occupancy combined with cross-species sequence analysis and transcript quantification, single lab\",\n      \"pmids\": [\"15607423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACACA (and ACACB) are direct binding targets of the environmental pollutant PFOA, identified by cysteine-reactive chemical proteomics probes; binding was verified by thermal shift assay and targeted proteomics (PRM), providing a mechanistic explanation for PFOA-induced abnormal fatty acid metabolism.\",\n      \"method\": \"Cysteine-targeting chemical proteomics (IAA and EBX probes), quantitative proteomics, parallel reaction monitoring (PRM), thermal shift assay, targeted metabolomics\",\n      \"journal\": \"Analytical chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal chemical proteomics and biophysical validation methods (chemical probe enrichment, PRM, thermal shift assay) in a single rigorous study\",\n      \"pmids\": [\"30134650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function mutations in ACACA reduce ACC1 protein level and enzyme activity in patient-derived cells, causing disrupted lipid homeostasis (altered lipidomic profile), impaired cell motility, and a neurodevelopmental syndrome (global developmental delay, microcephaly, hypotonia). Cell motility deficit was recapitulated by RNAi-mediated ACC1 knockdown in fibroblasts and was partially rescued by palmitate supplementation.\",\n      \"method\": \"Whole-exome sequencing, ACC1 enzyme activity assay in patient lymphocytes, lipidomics, cell proliferation/apoptosis/migration assays, siRNA knockdown, palmitate rescue\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzyme activity measured directly in patient cells, lipidomics, functional rescue with palmitate, and RNAi recapitulation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34552920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACACA knockdown in prostate cancer cells (DU145 and PC3) reduces proliferation, decreases mitochondrial ATP production, lowers mitochondrial DNA levels and MitoTracker staining, and elevates NAD+/NADH ratio and ROS levels, linking ACACA activity to mitochondrial function.\",\n      \"method\": \"siRNA knockdown, cell cycle and proliferation assays, mito-ATP measurement, mitochondrial staining (MitoTracker), mtDNA quantification, NAD+/NADH and ROS assays, xenograft tumor model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (metabolic, mitochondrial, in vivo) in a single lab study\",\n      \"pmids\": [\"33391420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Downregulation of ACACA in lung fibroblasts reduces acetylation of protein lysine residues and fatty acid synthesis, triggers a senescent and inflammatory phenotypic shift (SASP), and enables CXCL1-mediated recruitment of granulocytic myeloid-derived suppressor cells into the lung, thereby promoting formation of an immunosuppressive pre-metastatic niche. ACACA knock-in prevented lung metastasis in the MMTV-PyVT mouse model.\",\n      \"method\": \"Transcriptomics (microarray), lipidomics (LC-MS/MS), co-culture of lung fibroblasts with breast cancer cells, immunoblot, IHC, qRT-PCR, senescence assays (SA-β-Gal), ACACA knock-in mouse model\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway established with in vivo genetic rescue (knock-in), lipidomics, transcriptomics, and multiple cellular assays; in vivo confirmation with causal readout\",\n      \"pmids\": [\"36607556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Inhibition of ACACA in a lipid accumulation cell model reduces intracellular TG and TC, alleviates mitochondrial dysfunction (preserving MMP, ATP production, reducing ROS), and enhances fatty acid oxidation via activation of the AMPK–PPARα–CPT1A pathway.\",\n      \"method\": \"siRNA knockdown, CMS-121 pharmacological inhibitor, lipid quantification, mitochondrial function assays (MMP, ATP, ROS, MRC complex expression), AMPK/PPARα/CPT1A western blotting, high-fat diet mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and cellular readouts with both genetic and pharmacological inhibition in single lab\",\n      \"pmids\": [\"38395901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17A activates the mTORC2–ACACA signaling pathway in corpus cavernosum smooth muscle cells (CSMCs), upregulating lipid synthesis and senescence transition, leading to increased secretion of fibro-matrix proteins and fibrosis; blockade of this signaling improved erectile function in a neurogenic ED rat model.\",\n      \"method\": \"PCR array, western blotting, immunofluorescence, IHC, non-target metabolomics, siRNA, SA-β-Gal staining, in vivo rat neurogenic ED model with IL-17A antagonist\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway assignment via siRNA + metabolomics + in vivo pharmacological validation, single lab\",\n      \"pmids\": [\"39256772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AKR1B10 co-localizes with and regulates ACCα (ACACA) activity in hepatocytes; nicotinate-curcumin inhibits AKR1B10 binding to AKR1B10, reducing ACACA expression and activity, decreasing Malonyl-CoA levels, and thereby suppressing triglyceride and free fatty acid synthesis in NASH.\",\n      \"method\": \"Molecular docking, western blotting, immunofluorescence co-localization, ELISA (Acetyl-CoA and Malonyl-CoA activity), Ox-LDL-induced HepG2 cell model, rat NASH model\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization and pharmacological inhibition without direct protein-protein interaction validation (e.g., co-IP); molecular docking is computational\",\n      \"pmids\": [\"38937844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACACA depletion in androgen receptor-independent prostate cancer cells (via shRNA or TOFA inhibitor) elevates arachidonic acid and eicosanoid levels, increases cPLA2 expression, and activates NF-κB signaling, thereby enhancing cell migration and metastasis. Inhibiting cPLA2 or NF-κB reversed these pro-metastatic effects, placing ACACA upstream of the cPLA2–AA–NF-κB axis.\",\n      \"method\": \"shRNA knockdown, TOFA pharmacological inhibition, transcriptomics, metabolomics, single-cell RNA sequencing, qPCR, western blotting, immunofluorescence, wound healing and transwell assays, mouse tail vein metastasis model, targeted cPLA2/NF-κB inhibition\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis established via genetic + pharmacological inhibition with multiple orthogonal omics and in vivo validation, single lab\",\n      \"pmids\": [\"40713618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZXDB (RNA-binding protein) directly interacts with EIF4A3 via its aa151–300 region and recruits EIF4A3 to the ACACA 5'UTR to enhance ACACA translation; macrophage-specific Zxdb deletion reduces ACACA expression, attenuates pro-inflammatory cytokine secretion and glycolytic reprogramming, and alleviates sepsis-induced acute kidney injury in mice.\",\n      \"method\": \"Co-IP (ZXDB–EIF4A3 interaction with domain mapping), 5'UTR-dependent translation assay, macrophage-specific Zxdb knockout mouse model, SI-AKI model, qPCR, western blotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein–protein interaction with domain mapping, 5'UTR functional assay, and in vivo genetic knockout validation in single lab\",\n      \"pmids\": [\"41873808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IRX1 transcription factor interacts with NME1 and promotes NME1 nuclear localization; nuclear NME1 then facilitates IRX1-mediated transcriptional downregulation of ACACA, thereby suppressing de novo fatty acid synthesis and breast cancer progression. IRX1 promoter hypermethylation causes its loss in breast cancer.\",\n      \"method\": \"Co-IP (IRX1–NME1), subcellular fractionation/localization, reporter/ChIP assays for ACACA transcription, in vitro and in vivo (xenograft) tumor growth assays, siRNA/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP for protein interaction, localization experiment, transcriptional target validation, and in vivo confirmation, single lab\",\n      \"pmids\": [\"42225620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPRi screening identified ACACA as a key mediator of 1-deoxy-sphingolipid (1-deoxySL)-induced cellular toxicity; genetic knockdown validated that ACACA (involved in very long-chain fatty acid biosynthesis) modulates 1-deoxySL-induced cytotoxicity, mitochondrial toxicity, and neuronal toxicity.\",\n      \"method\": \"CRISPRi genome-wide screen, genetic knockdown validation, cytotoxicity assays, stable isotope-resolved lipidomics (LC-MS/MS)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPRi screen hit with knockdown validation but mechanistic follow-up for ACACA specifically is limited; preprint, not peer reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ACACA (ACC1/ACCα) is the rate-limiting enzyme catalyzing carboxylation of acetyl-CoA to malonyl-CoA, the first committed step in de novo fatty acid synthesis; its transcription is co-regulated by a bidirectional promoter shared with TADA2L and is induced by SREBP-1 acting cooperatively with the thyroid hormone receptor TR, while being suppressed by cAMP and medium-chain fatty acids; its protein is directly bound by PFOA (environmental pollutant) at reactive cysteines; upstream, ZXDB recruits EIF4A3 to the ACACA 5'UTR to enhance its translation, and IRX1-NME1 transcriptionally represses it; downstream, ACACA activity sustains mitochondrial function (ATP production, redox balance) and suppresses the AMPK–PPARα–CPT1A fatty acid oxidation axis, while ACACA depletion in androgen-receptor-independent prostate cancer paradoxically activates the cPLA2–arachidonic acid–NF-κB inflammatory axis to promote metastasis; in non-malignant fibroblasts, ACACA downregulation triggers a senescent/SASP phenotype via reduced protein acetylation and fatty acid synthesis, enabling immunosuppressive pre-metastatic niche formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACACA (ACC1/ACCα) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis, and its activity governs cellular lipid homeostasis, mitochondrial function, and the balance between fatty acid synthesis and oxidation [#3, #4, #6]. Its hepatic transcription is induced through cooperative binding of SREBP-1 and the thyroid hormone receptor at the ACACA promoter, an effect potentiated by T3 and insulin and suppressed by cAMP and medium-chain fatty acids acting through a defined cis-element (-101 to -71 bp) [#0]; the gene's 5' end lies in a CpG island containing a bidirectional promoter shared with the divergently transcribed TADA2L gene [#1]. ACACA is additionally controlled post-transcriptionally and post-translationally: the RNA-binding protein ZXDB recruits EIF4A3 to the ACACA 5'UTR to enhance its translation [#10], the transcription factor IRX1 together with nuclear NME1 represses its transcription [#11], and the environmental pollutant PFOA binds ACACA at reactive cysteines [#2]. Functionally, ACACA activity sustains mitochondrial ATP production, mtDNA levels, and redox balance while restraining the AMPK–PPARα–CPT1A fatty acid oxidation axis [#4, #6]; loss of ACACA elsewhere drives pathological phenotypes including a senescent SASP state in fibroblasts that recruits myeloid-derived suppressor cells to seed an immunosuppressive pre-metastatic niche [#5] and, in androgen-receptor-independent prostate cancer, activation of the cPLA2–arachidonic acid–NF-κB inflammatory axis that promotes metastasis [#9]. Biallelic loss-of-function mutations in ACACA reduce enzyme activity and cause a neurodevelopmental syndrome with global developmental delay, microcephaly, and hypotonia, with a cell-motility defect partially rescued by palmitate [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established how hormonal and nutritional signals converge on the ACACA promoter, identifying SREBP-1/TR cooperativity as the activating axis and a discrete cis-element mediating cAMP/medium-chain-fatty-acid repression.\",\n      \"evidence\": \"Reporter/transfection assays and SREBP-1 protein time-courses in hepatocytes under T3, insulin, cAMP, and hexanoate\",\n      \"pmids\": [\"12576518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to hepatocytes; tissue generality untested\", \"Does not address post-transcriptional regulation\", \"Endogenous chromatin occupancy of SREBP-1/TR not directly mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the genomic architecture of ACACA transcription, showing it shares a bidirectional CpG-island promoter with TADA2L and that asymmetric expression is set by Pol II clearance/elongation rather than promoter sequence alone.\",\n      \"evidence\": \"Cross-species 5' boundary delineation, Pol II ChIP in mouse brain vs. liver, transcript quantification\",\n      \"pmids\": [\"15607423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism controlling differential Pol II elongation unresolved\", \"Functional consequence of TADA2L co-regulation for ACACA unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that ACACA is a direct molecular target of an environmental pollutant, providing a chemical basis for PFOA-induced fatty acid metabolism abnormalities.\",\n      \"evidence\": \"Cysteine-reactive chemical proteomics with PRM and thermal shift validation\",\n      \"pmids\": [\"30134650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific reactive cysteine residues and effect on catalytic activity not fully resolved\", \"Physiological relevance of binding stoichiometry untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ACACA loss-of-function to a human Mendelian neurodevelopmental syndrome and demonstrated that its lipid output supports cell motility, establishing a causal genotype-phenotype connection.\",\n      \"evidence\": \"Whole-exome sequencing, patient-cell enzyme assays, lipidomics, RNAi recapitulation, and palmitate rescue\",\n      \"pmids\": [\"34552920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting reduced fatty acid synthesis to neurodevelopment not defined\", \"How palmitate restores motility molecularly unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected ACACA activity to mitochondrial bioenergetics and redox state in cancer cells, beyond its canonical biosynthetic role.\",\n      \"evidence\": \"siRNA knockdown in prostate cancer cells with mito-ATP, mtDNA, MitoTracker, NAD+/NADH, ROS readouts and xenografts\",\n      \"pmids\": [\"33391420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between malonyl-CoA output and mtDNA maintenance unclear\", \"Direct vs. indirect effect on mitochondria not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-cell-autonomous role: ACACA downregulation in fibroblasts induces senescence/SASP via reduced protein acetylation and lipid synthesis, recruiting MDSCs to build an immunosuppressive pre-metastatic niche.\",\n      \"evidence\": \"Transcriptomics, lipidomics, fibroblast–tumor co-culture, and an ACACA knock-in mouse rescuing lung metastasis\",\n      \"pmids\": [\"36607556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of acetyl-CoA limitation driving hypoacetylation not pinpointed\", \"Which acetylated targets mediate the SASP unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated reciprocal control of fatty acid oxidation: ACACA inhibition relieves the AMPK–PPARα–CPT1A axis to enhance oxidation and rescue lipid-overload mitochondrial dysfunction.\",\n      \"evidence\": \"siRNA plus CMS-121 inhibitor in a lipid-accumulation model with mitochondrial and AMPK/PPARα/CPT1A readouts and a high-fat-diet model\",\n      \"pmids\": [\"38395901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AMPK activation is via malonyl-CoA depletion not directly proven\", \"Tissue specificity of the response untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed ACACA downstream of IL-17A/mTORC2 signaling in driving lipid-synthesis-dependent senescence and fibrosis in smooth muscle.\",\n      \"evidence\": \"PCR array, siRNA, metabolomics, and an in vivo neurogenic ED rat model with IL-17A antagonist\",\n      \"pmids\": [\"39256772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking mTORC2 to ACACA regulation undefined\", \"Generalizability beyond cavernosum smooth muscle unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed AKR1B10 as a regulator of ACACA activity in hepatocytes relevant to NASH lipogenesis.\",\n      \"evidence\": \"Molecular docking, immunofluorescence co-localization, and ELISA-based malonyl-CoA assays in cell and rat NASH models\",\n      \"pmids\": [\"38937844\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-localization and docking without direct co-IP validation of physical interaction\", \"Mechanism by which AKR1B10 modulates ACACA activity unproven\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established epistasis placing ACACA upstream of the cPLA2–arachidonic acid–NF-κB axis, explaining how ACACA loss paradoxically promotes prostate cancer metastasis.\",\n      \"evidence\": \"shRNA/TOFA inhibition with transcriptomics, metabolomics, scRNA-seq, tail-vein metastasis, and rescue by cPLA2/NF-κB blockade\",\n      \"pmids\": [\"40713618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How reduced malonyl-CoA liberates arachidonic acid for cPLA2 not mechanistically defined\", \"Restricted to AR-independent prostate cancer context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified post-transcriptional activation of ACACA: ZXDB recruits EIF4A3 to the 5'UTR to boost translation, coupling ACACA to macrophage inflammatory and glycolytic reprogramming.\",\n      \"evidence\": \"Co-IP with domain mapping, 5'UTR-dependent translation assay, and macrophage-specific Zxdb knockout in a sepsis-AKI model\",\n      \"pmids\": [\"41873808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of ZXDB/EIF4A3 to the ACACA 5'UTR vs. indirect effect not fully separated\", \"Whether translational control operates in non-macrophage cells unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a transcriptional repression module in which IRX1 and nuclear NME1 downregulate ACACA to restrain de novo lipogenesis and breast cancer progression.\",\n      \"evidence\": \"Reciprocal co-IP, subcellular fractionation, reporter/ChIP for ACACA, and xenograft assays\",\n      \"pmids\": [\"42225620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of IRX1/NME1 to the ACACA promoter region not finely mapped\", \"Role of NME1 nucleotide-kinase activity in repression unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse upstream regulators (SREBP-1/TR, ZXDB/EIF4A3, IRX1/NME1, AKR1B10) are integrated to set ACACA output in a given tissue, and how malonyl-CoA depletion mechanistically rewires mitochondrial bioenergetics and eicosanoid signaling, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model integrating transcriptional, translational, and post-translational control\", \"Structural basis of regulator binding and PFOA modification not determined\", \"Causal chain from malonyl-CoA levels to downstream phenotypes incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SREBP-1\", \"THRA\", \"AKR1B10\", \"ZXDB\", \"EIF4A3\", \"IRX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}