{"gene":"CPT1A","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2011,"finding":"CPT1A exists in the liver mitochondrial outer membrane as part of a large protein complex containing long-chain acyl-CoA synthetase (ACSL) and voltage-dependent anion channel (VDAC), identified by blue native electrophoresis, immunoblotting, mass spectrometry, and reciprocal immunoprecipitation. This complex is proposed to transfer activated fatty acids through the outer mitochondrial membrane.","method":"Blue native PAGE, immunoblotting, mass spectrometry, co-immunoprecipitation with antisera against each protein","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, blue native PAGE, and MS all converge on the same complex in a single rigorous study","pmids":["21622568"],"is_preprint":false},{"year":2010,"finding":"PPARα activates CPT1A transcription through a binding site in the second intron of the rat CPT1A gene, while PGC-1α activates CPT1A through a separate element in the first intron; these two regulators act via independent gene elements and do not cooperate through each other's binding sites.","method":"Luciferase reporter assays, PPARα binding site mutation, WY14643 ligand treatment, PGC-1α shRNA knockdown, in vivo fasted rat liver transfection","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific intronic elements, in vitro and in vivo reporter assays, shRNA knockdown, multiple orthogonal methods","pmids":["20638986"],"is_preprint":false},{"year":2018,"finding":"CPT1A interacts with Rab14, and this interaction facilitates fatty acid trafficking from lipid droplets to mitochondria in NPC cells, thereby reducing radiation-induced lipid accumulation and maximizing ATP production to promote radiation resistance.","method":"LC-MS/MS protein identification, co-immunoprecipitation, immunofluorescence, in situ proximity ligation assay, computational docking, pulse-chase fatty acid trafficking assay with BODIPY C16 and MitoTracker Red, Rab14 knockdown","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, proximity ligation, functional rescue with multiple orthogonal methods in one study","pmids":["29721083"],"is_preprint":false},{"year":2021,"finding":"Butyrate is converted by ACSS2 to butyryl-CoA (BCoA), which antagonizes the binding of malonyl-CoA at Arg243 of CPT1A, thereby upregulating CPT1A activity and promoting fatty acid oxidation and iTreg differentiation. Mutation of CPT1A Arg243 impairs both malonyl-CoA and butyryl-CoA binding, identifying this residue as the responsible site.","method":"In vitro CPT1A activity assays, site-directed mutagenesis of Arg243, ACSS2 inhibitor, iTreg differentiation assays, mouse colitis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with enzymatic activity assay, pharmacologic inhibition, and in vivo functional validation","pmids":["34035164"],"is_preprint":false},{"year":2018,"finding":"CPT1A functions as a lysine succinyltransferase (LSTase), interacting with S100A10 and succinylating it at Lys47, which stabilizes S100A10 by suppressing ubiquitylation and proteasomal degradation, thereby promoting gastric cancer cell invasion and migration. Desuccinylation is mediated by SIRT5.","method":"Co-immunoprecipitation, mass spectrometry identification of succinylation site, succinylation mimetic mutant (K47E) overexpression, cell invasion/migration assays, knockdown experiments","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS identification of PTM, functional mutant, single lab","pmids":["30394687"],"is_preprint":false},{"year":2022,"finding":"Mitochondrial STAT3 stabilizes CPT1A protein by abrogating its ubiquitination and degradation in LPS-treated macrophages. This stabilization is mediated through CPT1A interaction with ubiquitin-specific peptidase 50 (USP50), whose promoter is bound by NF-κB (downstream of mitochondrial STAT3), thereby linking mitochondrial STAT3 to FAO-dependent metabolic reprogramming in sepsis.","method":"Mass spectrometry, co-immunoprecipitation (CPT1A–USP50 interaction), ChIP assay (NF-κB at USP50 promoter), USP50 knockdown, metabolic assays, knock-in mouse model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic knockdown, knock-in mouse, multiple orthogonal methods","pmids":["34976224"],"is_preprint":false},{"year":2023,"finding":"CPT1A recruits the ER-localized palmitoyltransferase ZDHHC4 to catalyze MAVS palmitoylation at Cys79, which promotes MAVS stabilization and activation by inhibiting K48-linked ubiquitination while facilitating K63-linked ubiquitination, thereby amplifying the type I interferon response. This is a non-FAO enzymatic function of CPT1A.","method":"Co-immunoprecipitation (CPT1A–ZDHHC4 and CPT1A–MAVS), palmitoylation assays, mutagenesis of MAVS Cys79, ubiquitination assays (K48 vs K63), genetic overexpression/depletion, in vivo tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of palmitoylation pathway with mutagenesis, multiple Co-IPs, ubiquitination characterization, and in vivo validation in one rigorous study","pmids":["38016475"],"is_preprint":false},{"year":2021,"finding":"CPT1A-dependent fatty acid oxidation promotes β-catenin acetylation and nuclear translocation in colon cancer cells exposed to adipocytes or fatty acids, activating Wnt/β-catenin target genes associated with cancer stemness.","method":"CPT1A siRNA knockdown, β-catenin nuclear translocation assays, p300 inhibitor rescue, 3D organoid culture, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with defined pathway readout, pharmacologic rescue with p300 inhibitor, in vivo validation, single lab","pmids":["32913185"],"is_preprint":false},{"year":2019,"finding":"CPT1A overexpression in prostate cancer cells increases histone acetylation by supplying acetyl groups, supporting castration-resistant growth; this histone acetylation increase is partially reversed by a p300-specific inhibitor, indicating a link between lipid catabolism and epigenetic regulation.","method":"CPT1A overexpression and knockdown cell lines, histone acetylation analysis, p300 inhibitor treatment, androgen deprivation experiments, tumor growth assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic OE/KD with defined epigenetic readout and pharmacologic rescue, single lab","pmids":["31547059"],"is_preprint":false},{"year":2021,"finding":"Cpt1a overexpression in renal tubular epithelial cells (TECs) restores oxidative metabolism and mitochondrial number, increases palmitate oxidation and ATP levels, reduces fibrotic marker expression and macrophage influx in three mouse models of renal fibrosis, establishing that gain-of-function in CPT1A-mediated FAO is sufficient to protect against fibrosis.","method":"Conditional transgenic CPT1A knock-in mouse, three fibrosis models (UUO, FAN, adenine nephrotoxicity), palmitate oxidation assays, ATP measurements, histology, gene expression","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional transgenic model replicated across three independent injury models with biochemical readouts","pmids":["33465052"],"is_preprint":false},{"year":2023,"finding":"CPT1A-dependent FAO in cancer cells is induced by T cell-derived IFN-γ in an AMPK-dependent manner and confers resistance to cytotoxic T lymphocyte killing by maintaining prosurvival signaling. Genetic repression or pharmacologic inhibition of CPT1A renders tumors more susceptible to CAR-T cell therapy.","method":"CPT1A knockout and knockdown, IFN-γ treatment, AMPK inhibition, co-culture cytotoxicity assays, CAR-T cell therapy in tumor-bearing mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, defined upstream signal (IFN-γ/AMPK), in vitro and in vivo functional readouts","pmids":["37722058"],"is_preprint":false},{"year":2023,"finding":"CPT1A directly binds PHB2 in the mitochondria and modulates the PHB2-PARL interaction; increased CPT1A activity (induced by L-carnitine or amino acid mutation M593S) enhances the PHB2-PARL interaction and thereby promotes PINK1-Parkin-dependent mitophagy, improving mitochondrial function in diabetic cardiomyopathy.","method":"Co-immunoprecipitation (CPT1A–PHB2), adenovirus-mediated overexpression of WT and M593S mutant CPT1A, PARL overexpression rescue, immunofluorescence, transmission electron microscopy, db/db mouse model","journal":"Acta physiologica (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, gain-of-function mutant, rescue experiments, in vivo model, single lab","pmids":["37042471"],"is_preprint":false},{"year":2021,"finding":"Hepatocyte-specific Cpt1a knockout in mice activates the PPARα-FGF21 axis, elevating circulating FGF21, which drives adipose browning and increased energy expenditure; antibody-mediated FGF21 neutralization abolishes these effects, establishing a CPT1A-mediated liver-adipose cross-talk pathway.","method":"Liver-specific Cpt1a knockout mice, RNAseq, anti-FGF21 antibody neutralization, metabolic phenotyping, adipose tissue analysis","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, RNAseq pathway identification, antibody rescue confirming FGF21 mediates the phenotype","pmids":["34675003"],"is_preprint":false},{"year":2023,"finding":"CPT1A directly interacts with Bcl-2 at its BH3 domain, anchoring Bcl-2 in the mitochondria in an activity-dependent manner to attenuate apoptosis in lung macrophages; disruption of this interaction induces apoptosis and reduces pulmonary fibrosis.","method":"Co-immunoprecipitation, CPT1A activity inhibition, Bcl-2 macrophage-specific deletion, bleomycin fibrosis mouse model, ABT-199 pharmacologic inhibition","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying BH3 domain interaction, activity-dependence demonstrated, genetic and pharmacologic validation in vivo","pmids":["34413485"],"is_preprint":false},{"year":2019,"finding":"Ethanol induces repressive H3K9 deacetylation at the CPT1A promoter via HDAC1 recruitment mediated by SP1 (proximal region) and HNF4α (distal region); butyrate/tributyrin inhibits HDAC1 and facilitates p300 binding at these same sites, restoring CPT1A transcription and reducing hepatic steatosis.","method":"Chromatin immunoprecipitation (ChIP) in vivo (mouse liver) and in vitro (primary hepatocytes), ethanol and butyrate treatment, histone modification analysis","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP identifying specific HDAC1 and HAT binding at CPT1A promoter, validated in vivo and in vitro with mechanistic resolution of proximal/distal elements","pmids":["31654770"],"is_preprint":false},{"year":2023,"finding":"SIRT1 directly deacetylates CPT1A at Lys675, which suppresses ubiquitin-dependent degradation of CPT1A and promotes FAO; berberine increases SIRT1 expression, which in turn increases CPT1A protein level and activity to alleviate NAFLD.","method":"Co-immunoprecipitation (SIRT1–CPT1A) in HEK293T cells, CPT1A activity assay, site identification at Lys675, SIRT1 overexpression/knockdown","journal":"Gastroenterology report","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying interaction, site-level PTM characterization, functional assays, single lab","pmids":["37293270"],"is_preprint":false},{"year":2018,"finding":"High-fructose feeding induces hypermethylation of the CPT1A promoter region, associated with reduced CPT1A mRNA expression and hepatic lipid accumulation in rats.","method":"qAMP restriction digestion and real-time PCR methylation analysis, real-time PCR for mRNA quantification, rat dietary model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single epigenetic readout method (qAMP) in a single dietary model, no mechanistic dissection of the methylation writers/erasers","pmids":["26519879"],"is_preprint":false},{"year":2018,"finding":"High-fat diet elevates hepatic Cpt1a expression through coordinated epigenetic mechanisms: reduced DNA methylation and increased H3K4Me2 upstream/within the promoter, accompanied by increased PPARα, C/EBPβ, PGC-1α, and BAF60a (SMARCD1) binding in the first intron at the transcription start site region.","method":"Bisulfite sequencing (DNA methylation), ChIP (H3K4Me2, PPARα, C/EBPβ, PGC-1α, BAF60a), rat dietary model, NEFA-treated H4IIEC3 hepatoma cells","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and methylation analysis with multiple histone and transcription factor targets, in vivo and in vitro validation, single lab","pmids":["30605728"],"is_preprint":false},{"year":2020,"finding":"Liver-targeted AAV delivery of a permanently active mutant form of human CPT1A (hCPT1AM) enhances hepatic FAO and autophagy, reduces liver steatosis, and improves glucose homeostasis in a mouse model of established obesity and NAFLD.","method":"AAV9-hCPT1AM gene delivery, FAO assays, lipidomic analysis, metabolic phenotyping in HFD mice","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function gene therapy with biochemical readouts in vivo, single lab","pmids":["32666604"],"is_preprint":false},{"year":2009,"finding":"CPT1A catalyzes the rate-limiting step of long-chain fatty acid oxidation: transfer of long-chain acyl groups from acyl-CoA to carnitine, generating acylcarnitines that cross the inner mitochondrial membrane. The enzyme is inhibited allosterically by malonyl-CoA.","method":"Review synthesizing enzymatic activity assays and biochemical studies (multiple prior studies summarized in review context)","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic function established by decades of in vitro enzymatic assays and mutational studies across multiple labs, confirmed in this comprehensive review","pmids":["31900483"],"is_preprint":false},{"year":2018,"finding":"Genetic deletion of Cpt1a specifically in T cells demonstrates that the ACC2/Cpt1a axis is largely dispensable for effector, memory, and regulatory T cell formation, and that the effects of etomoxir on T cell differentiation are independent of Cpt1a expression.","method":"T cell-specific Cpt1a genetic knockout mice, primary/memory/regulatory T cell functional assays, etomoxir treatment comparison","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with multiple T cell subset readouts; negative finding robustly established by genetic model","pmids":["30043753"],"is_preprint":false},{"year":2024,"finding":"CPT1A restrains ubiquitination and degradation of c-Myc, while c-Myc transcriptionally activates CPT1A expression, forming a positive feedback loop that activates the NRF2/GPX4 antioxidant system and downregulates ACSL4, thereby suppressing ferroptosis in lung cancer stem cells.","method":"Lung epithelial-specific Cpt1a-knockout mouse model, metabolomics, transcriptomics, co-immunoprecipitation (CPT1A–c-Myc), ubiquitination assays, NRF2/GPX4/ACSL4 expression analysis","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic KO mouse, pathway analysis; feedback loop supported but with limited direct mutagenesis to dissect each step","pmids":["38453925"],"is_preprint":false},{"year":2023,"finding":"A novel covalent inhibitor DHP-B binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 protein interaction, leading to increased mitochondrial permeability and reduced oxygen consumption in colorectal cancer cells.","method":"Covalent binding characterization, Cys96 identification, CPT1A-VDAC1 co-immunoprecipitation, oxygen consumption assay, mitochondrial permeability measurement, in vitro and in vivo tumor models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — covalent inhibitor site identification, Co-IP for CPT1A-VDAC1 interaction, functional assays, single lab","pmids":["37977042"],"is_preprint":false},{"year":2022,"finding":"CPT1A-mediated FAO in osteoclast precursors promotes their fusion by increasing expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) through enhanced binding of transcription factor C/EBPβ to CLTA and CLTC promoters, thereby driving clathrin-dependent endocytosis and podosome formation.","method":"CPT1A overexpression/knockdown, C/EBPβ ChIP at CLTA/CLTC promoters, clathrin expression analysis, osteoclast fusion and podosome assays, RA patient samples","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP linking FAO to transcription factor binding, genetic manipulation, defined cellular phenotype, single lab","pmids":["35273614"],"is_preprint":false},{"year":2023,"finding":"CPT1A loss reduces acetyl-CoA production, which decreases histone acetylation and epigenetically reprograms BCAA catabolism, leading to BCAA accumulation and hyperactivation of mTOR signaling in TP53-mutant hepatocellular carcinoma; this renders cells sensitive to the mTOR inhibitor AZD-8055.","method":"CPT1A genetic ablation (de novo liver tumor and xenograft models), acetyl-CoA measurement, histone acetylation analysis, BCAA metabolomics, mTOR pathway analysis, mTOR inhibitor treatment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics, histone acetylation measurements, genetic ablation, pathway epistasis, single lab","pmids":["38823763"],"is_preprint":false},{"year":2023,"finding":"FOXA1 transcriptionally promotes CPT1A expression by binding a cis-inducible element in the CPT1A promoter, as demonstrated by ChIP and dual-luciferase reporter assays; FOXA1-mediated CPT1A upregulation promotes FAO and alleviates ferroptosis in renal tubular epithelial cells under diabetic conditions.","method":"Chromatin immunoprecipitation assay, dual-luciferase reporter gene assay, FOXA1 overexpression/knockdown, CPT1A activity and FAO assays, diabetic mouse model","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and luciferase reporter directly demonstrating FOXA1 binding to CPT1A promoter, functional validation, single lab","pmids":["38128823"],"is_preprint":false},{"year":2025,"finding":"CPT1A uses its lysine succinyltransferase (LSTase) activity to succinylate mitochondrial fission factor (MFF), which promotes mitochondria-associated membrane formation and SREBP1 activation, leading to SCD1 upregulation and lipid desaturation essential for ovarian cancer stem cell stemness maintenance.","method":"Co-immunoprecipitation (CPT1A–MFF), succinylation assays, SREBP1 activation assays, SCD1 expression analysis, LSTase activity inhibition with Glyburide, in vitro and in vivo stemness assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PTM assays, pharmacologic LSTase inhibition, functional stemness readout, single lab","pmids":["39956875"],"is_preprint":false},{"year":2022,"finding":"Cpt1a-dependent mitochondrial fatty acid oxidation is required for neutrophil chemotaxis; pharmacologic inhibition of Cpt1a impairs chemoattractant signal amplification, blunts neutrophil trafficking to sites of infection, and increases susceptibility to bacterial pneumonia in mice.","method":"Pharmacologic Cpt1a inhibition in murine pneumonia model, neutrophil chemotaxis assays, human phenome association study for pneumonia risk variant","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic inhibition with defined cellular phenotype (chemotaxis), in vivo infection model, human genetic association corroboration","pmids":["36513703"],"is_preprint":false},{"year":2023,"finding":"CPT1A in AgRP neurons is required for sex-dependent regulation of food intake, energy expenditure, and fluid balance; male Cpt1aKO mice show altered food intake while female Cpt1aKO mice show increased energy expenditure and brown adipose tissue activity; both sexes develop polydipsia and polyuria with reduced vasopressin levels. AgRP neurons from Cpt1aKO mice show reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus.","method":"AgRP neuron-specific Cpt1a knockout (tamoxifen-inducible AgRPCreERT2), metabolic phenotyping, calorimetry, AAV-mediated neuronal labeling, RiboTag ribosome profiling, single-nucleus RNA-seq","journal":"Biology of sex differences","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with comprehensive metabolic, neuroanatomical, and molecular phenotyping","pmids":["36966335"],"is_preprint":false},{"year":2024,"finding":"Tubule-specific Cpt1a deletion in mice does not significantly affect kidney function or fibrosis after aging or chronic injury; primary tubule cells lacking Cpt1a show modest reduction in palmitate oxidation but compensate through upregulation of peroxisomal FAO enzymes, suggesting peroxisomal β-oxidation compensates for loss of mitochondrial CPT1A-mediated FAO in tubules.","method":"Tubule-specific Cpt1a conditional KO mice, aristolochic acid and UUO injury models, 2-year aging, single-nuclear RNA-Seq, palmitate oxidation assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple injury models and aging, snRNA-Seq, biochemical oxidation assays; well-controlled negative/compensatory finding","pmids":["38516886"],"is_preprint":false},{"year":2024,"finding":"ALKBH5 demethylase removes m6A modification from CPT1A mRNA, enhancing its stability and upregulating CPT1A expression in macrophages, which promotes M2 macrophage polarization and FAO, facilitating colorectal cancer progression.","method":"Me-RIP assay, Actinomycin D mRNA stability assay, ALKBH5 gain-of-function, OCR measurement, co-culture CRC/macrophage model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Me-RIP and mRNA stability assays directly demonstrating m6A regulation of CPT1A mRNA, functional assays, single lab","pmids":["38479704"],"is_preprint":false},{"year":2024,"finding":"CPT1A promotes K63-type ubiquitination of IGF2BP1 via RNF5; IGF2BP1 then binds m6A sites on CPT1A mRNA and enhances its stability, creating a regulatory axis (PPARγ-RNF5-IGF2BP1-CPT1A) in steatotic hepatocellular carcinoma that sustains FAO.","method":"RNF5–IGF2BP1 interaction assays, K63-ubiquitination characterization, m6A-RIP for CPT1A mRNA, mRNA stability assays, PPARγ ChIP at RNF5 promoter, lipidomics, transcriptomics","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP/ubiquitination assays, m6A-RIP, ChIP for upstream regulation; single lab but orthogonal methods","pmids":["39734009"],"is_preprint":false},{"year":2024,"finding":"PACS2 positively regulates CPT1A expression; PACS2 silencing downregulates CPT1A and upregulates DHODH, reversing HGPA-induced ferroptosis in cardiomyocytes. CPT1A agonist treatment in PACS2-silenced cells re-exacerbates ferroptosis and mitochondrial damage, placing CPT1A downstream of PACS2 in the PACS2/CPT1A/DHODH ferroptosis signaling pathway.","method":"PACS2 siRNA knockdown, CPT1A agonist rescue, ferroptosis markers (iron, lipid peroxides, ROS), STZ/HFD diabetic mouse model, cardiac function measurement","journal":"Cardiovascular diabetology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with pharmacologic rescue establishing pathway order, in vivo mouse model, single lab","pmids":["39633391"],"is_preprint":false},{"year":2024,"finding":"Astragaloside IV (ASIV) restores CPT1A activity, which in turn mediates K99 succinylation of HSD17B10; this succinylation maintains mitochondrial RNase P stability by stabilizing the HSD17B10-MRPP1 interaction. K99R mutation of HSD17B10 disrupts its binding to CPT1A and MRPP1, impairs RNase P activity, and induces oxidative stress. Molecular docking and cell thermal shift assay suggest ASIV directly binds CPT1A.","method":"Succinylated proteomics, site-directed mutagenesis (K99R), molecular docking, cell thermal shift assay, Co-IP (HSD17B10–CPT1A, HSD17B10–MRPP1), RNase P activity assay, db/db mouse model","journal":"Phytotherapy research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM proteomics, site mutagenesis, Co-IP, thermal shift; single lab","pmids":["39038923"],"is_preprint":false},{"year":2024,"finding":"CPT1A anchors Bcl2 to the mitochondrial membrane in podocytes, preventing cytochrome C release and mitochondrial apoptosis; CPT1A also fosters lipid consumption via FAO, reducing lipotoxicity. FOXA1 is identified as a transcription factor for CPT1A in podocytes. CPT1A overexpression protects against albuminuria and glomerulosclerosis in diabetic mice.","method":"CPT1A overexpression, streptozotocin diabetic mouse model, Bcl2 mitochondrial localization assay, cytochrome C release assay, FOXA1 identification as upstream regulator","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in vivo with defined molecular mechanisms (Bcl2 anchoring, FOXA1 regulation), single lab","pmids":["38506804"],"is_preprint":false},{"year":2012,"finding":"A novel homozygous missense mutation R595W in CPT1A reduces CPT1A enzymatic activity by inducing steric hindrance: Arg595 contributes to a hydrogen-bond network with Cys304 and Met593, and its replacement by tryptophan causes steric clash with Ile480 in α-helix 12, disrupting protein architecture and function without directly affecting the catalytic site or carnitine pocket.","method":"CPT1A activity assay in patient fibroblasts, sequence alignment, protein structural modeling, comparison with known C304W mutant mechanism","journal":"JIMD reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — enzymatic activity measurement in patient cells combined with structural modeling; mechanistic insight from modeling without crystal structure","pmids":["23430932"],"is_preprint":false},{"year":2023,"finding":"CPT1A-mediated FAO promotes VEGF-C and VEGF-D expression in breast cancer cells and regulates VEGFR3 expression in lymphatic endothelial cells via acetyl-CoA-mediated H3K9 acetylation, promoting lymphangiogenesis; acetate supplementation rescues VEGFR3 expression upon CPT1A knockdown.","method":"CPT1A shRNA knockdown, LC-MS acetyl-CoA/CoA ratio measurement, VEGF-C/D and VEGFR3 expression analysis, H3K9ac analysis, acetate rescue, transwell and lymphatic vessel formation assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolite measurement (acetyl-CoA), epigenetic readout (H3K9ac), and acetate rescue connecting FAO to histone modification and VEGFR3; single lab","pmids":["29940537"],"is_preprint":false},{"year":2024,"finding":"Coriobacteriaceae bacteria (Cori.ST1911) activate CPT1A and increase acylcarnitine levels in colorectal cancer cells via the CPT1A-ERK signaling pathway, promoting tumorigenesis; this was demonstrated in CRC cell lines, organoids, and multiple CRC mouse models.","method":"16S rRNA and metagenomic sequencing, LC-MS/MS metabolomics, CRC cell/organoid co-culture with Coriobacteriaceae, CPT1A-ERK pathway analysis, multiple CRC mouse models","journal":"NPJ biofilms and microbiomes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway analysis in multiple model systems with metabolomic validation; single lab","pmids":["38245554"],"is_preprint":false},{"year":2024,"finding":"CPT1A mediates chemoresistance in hypopharyngeal squamous cell carcinoma by interacting with autophagy-related protein ATG16L1 and stimulating its succinylation, which drives autophagosome formation and autophagy; 3-methyladenine (autophagy inhibitor) or CPT1A inhibitor reduces cisplatin resistance.","method":"Co-immunoprecipitation (CPT1A–ATG16L1), succinylation assays, 3-MA autophagy inhibitor treatment, CPT1A inhibitor treatment, in vitro and in vivo cisplatin sensitivity assays","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, succinylation characterization, pharmacologic rescue; single lab","pmids":["37961047"],"is_preprint":false},{"year":2022,"finding":"STAT3/CPT1A-dependent FAO sustains hepatic stellate cell (HSC) proliferation and activation; cryptotanshinone inhibits STAT3 phosphorylation and nuclear translocation, reducing CPT1A expression and FAO (measured by ATP and acetyl-CoA reduction), with CPT1A overexpression reversing the anti-fibrotic effect.","method":"Transcriptomic sequencing, CPT1A and CPT1B expression analysis, STAT3 phosphorylation and nuclear translocation assay, ATP and acetyl-CoA measurement, CPT1A overexpression rescue, CCl4 mouse fibrosis model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by pharmacologic inhibition and genetic rescue, metabolite measurement; single lab","pmids":["38936533"],"is_preprint":false}],"current_model":"CPT1A is the rate-limiting outer mitochondrial membrane enzyme that transfers long-chain acyl groups from acyl-CoA to carnitine (generating acylcarnitines for inner-membrane transport), is allosterically inhibited by malonyl-CoA at Arg243, forms a complex with ACSL and VDAC in the outer membrane to channel activated fatty acids, and also possesses a lysine succinyltransferase activity that post-translationally modifies substrates (S100A10, MFF, ATG16L1, HSD17B10); its transcription is independently activated by PPARα (second intron) and PGC-1α (first intron), regulated epigenetically by HDAC1/SIRT1 and DNA methylation, and its protein stability is controlled by USP50-mediated deubiquitination (downstream of mitochondrial STAT3/NF-κB) and SIRT1-mediated deacetylation at Lys675, while non-canonically it recruits ZDHHC4 to palmitoylate MAVS at Cys79, stabilizing innate immune signaling, and interacts with Bcl-2 (BH3 domain), Rab14, PHB2, VDAC1, c-Myc, and ATG16L1 to regulate apoptosis, fatty acid trafficking, mitophagy, and autophagy across multiple cell types."},"narrative":{"mechanistic_narrative":"CPT1A is the rate-limiting outer mitochondrial membrane enzyme of long-chain fatty acid oxidation (FAO), transferring long-chain acyl groups from acyl-CoA to carnitine to generate acylcarnitines for inner-membrane import, and is allosterically inhibited by malonyl-CoA [PMID:31900483]. It does not act alone in the membrane: it assembles into a complex with long-chain acyl-CoA synthetase (ACSL) and the channel VDAC that funnels activated fatty acids through the outer membrane [PMID:21622568], and the CPT1A–VDAC1 interaction is itself required for normal mitochondrial permeability and respiration [PMID:37977042]. Malonyl-CoA sensitivity and catalysis converge on defined residues—malonyl-CoA and the antagonist butyryl-CoA both bind Arg243 [PMID:34035164], a covalent inhibitor engages Cys96 [PMID:37977042], and a disease-causing R595W substitution disrupts protein architecture remote from the catalytic pocket [PMID:23430932]. Beyond its catalytic role, CPT1A is a moonlighting protein: it possesses lysine succinyltransferase activity that modifies and stabilizes diverse substrates including S100A10, mitochondrial fission factor MFF, ATG16L1, and HSD17B10 to influence migration, lipid desaturation, autophagy, and mitochondrial RNase P stability [PMID:30394687, PMID:39956875, PMID:37961047, PMID:39038923], and it serves as a scaffold that recruits ZDHHC4 to palmitoylate MAVS at Cys79, stabilizing innate immune signaling [PMID:38016475]. CPT1A also anchors Bcl-2 at the mitochondria through its BH3 domain in an activity-dependent manner to restrain apoptosis [PMID:34413485], and binds PHB2 to promote PINK1/Parkin-dependent mitophagy [PMID:37042471]. Through the acetyl-CoA generated by FAO, CPT1A links lipid catabolism to epigenetic regulation, supplying acetyl groups for histone acetylation and Wnt/β-catenin and VEGFR3 signaling [PMID:32913185, PMID:31547059, PMID:29940537]. CPT1A expression is transcriptionally driven by PPARα and PGC-1α through independent intronic elements [PMID:20638986] and by FOXA1 [PMID:38128823], controlled epigenetically via HDAC1/p300 and DNA methylation [PMID:31654770], and its protein stability is governed by USP50-mediated deubiquitination downstream of mitochondrial STAT3/NF-κB [PMID:34976224] and SIRT1-mediated deacetylation at Lys675 [PMID:37293270]. Physiologically, CPT1A-mediated FAO mediates liver–adipose crosstalk via the PPARα–FGF21 axis [PMID:34675003], regulates AgRP-neuron control of feeding and energy balance [PMID:36966335], drives neutrophil chemotaxis [PMID:36513703], and is protective in renal and cardiac disease models [PMID:33465052, PMID:38506804], though tissue-specific knockouts reveal substantial functional redundancy with peroxisomal β-oxidation in kidney tubules and dispensability in T cells [PMID:38516886, PMID:30043753].","teleology":[{"year":2009,"claim":"Established CPT1A as the rate-limiting, malonyl-CoA-inhibited enzyme that commits long-chain fatty acids to mitochondrial oxidation, defining the baseline catalytic function on which all later work builds.","evidence":"Synthesis of enzymatic activity and biochemical studies in a comprehensive review","pmids":["31900483"],"confidence":"High","gaps":["Does not resolve residue-level determinants of malonyl-CoA sensitivity or catalysis","Review context rather than a single new experiment"]},{"year":2010,"claim":"Resolved how CPT1A transcription is controlled, showing PPARα and PGC-1α act through separate, non-cooperating intronic elements rather than a single regulatory module.","evidence":"Luciferase reporters, intronic element mutagenesis, ligand treatment, shRNA, and in vivo rat liver transfection","pmids":["20638986"],"confidence":"High","gaps":["Does not address protein-level or epigenetic regulation","Defined in rat gene; human element conservation not tested here"]},{"year":2011,"claim":"Showed CPT1A is not an isolated enzyme but a member of an outer-membrane ACSL–VDAC complex, providing a structural basis for channeling activated fatty acids across the membrane.","evidence":"Blue native PAGE, MS, and reciprocal Co-IP from liver mitochondria","pmids":["21622568"],"confidence":"High","gaps":["Stoichiometry and architecture of the complex not determined","Functional channeling proposed but not directly reconstituted"]},{"year":2012,"claim":"Linked CPT1A to a Mendelian metabolic disorder by defining how a homozygous R595W substitution impairs enzyme activity through steric disruption rather than catalytic-site loss.","evidence":"Activity assay in patient fibroblasts plus structural modeling","pmids":["23430932"],"confidence":"Medium","gaps":["No crystal structure to confirm modeled steric clash","Single patient genotype"]},{"year":2018,"claim":"Revealed the first moonlighting enzymatic function of CPT1A—lysine succinyltransferase activity—by showing it succinylates and stabilizes S100A10 to promote cancer cell invasion.","evidence":"Co-IP, MS site identification, succinyl-mimetic mutant, invasion assays, SIRT5 desuccinylation","pmids":["30394687"],"confidence":"Medium","gaps":["Single lab; catalytic mechanism of succinyltransferase activity not dissected","Relationship to the canonical acyltransferase active site unclear"]},{"year":2018,"claim":"Demonstrated a non-enzymatic trafficking role by showing CPT1A binds Rab14 to deliver fatty acids from lipid droplets to mitochondria, coupling lipid handling to radioresistance.","evidence":"LC-MS/MS, reciprocal Co-IP, proximity ligation, BODIPY-C16 pulse-chase, Rab14 knockdown","pmids":["29721083"],"confidence":"High","gaps":["Direct binding interface not mapped","Generality beyond NPC cells untested"]},{"year":2018,"claim":"Tempered overinterpretation of FAO in immunity by genetically showing CPT1A is largely dispensable for T cell differentiation and that etomoxir effects are CPT1A-independent.","evidence":"T cell-specific Cpt1a knockout with multiple subset readouts and etomoxir comparison","pmids":["30043753"],"confidence":"High","gaps":["Does not exclude roles in other immune cell types","Compensatory pathways not characterized"]},{"year":2019,"claim":"Connected CPT1A-derived acetyl-CoA to epigenetic reprogramming, showing FAO supplies acetyl groups for histone acetylation supporting castration-resistant prostate cancer growth.","evidence":"Overexpression/knockdown, histone acetylation analysis, p300 inhibitor rescue","pmids":["31547059"],"confidence":"Medium","gaps":["Single lab; direct acetyl-CoA flux to histones not traced","Specific histone loci not defined"]},{"year":2019,"claim":"Established epigenetic control of CPT1A transcription, mapping HDAC1 recruitment via SP1/HNF4α and p300-mediated reversal by butyrate at defined promoter regions.","evidence":"In vivo and in vitro ChIP with ethanol and butyrate treatment","pmids":["31654770"],"confidence":"High","gaps":["Does not address protein-level regulation","Studied in alcoholic steatosis context"]},{"year":2021,"claim":"Provided active-site resolution of CPT1A regulation by showing butyryl-CoA competes with malonyl-CoA at Arg243 to activate FAO and drive iTreg differentiation.","evidence":"In vitro activity assays, Arg243 mutagenesis, ACSS2 inhibition, iTreg and colitis models","pmids":["34035164"],"confidence":"High","gaps":["Structural basis of dual-ligand binding at Arg243 not crystallographically resolved"]},{"year":2021,"claim":"Established CPT1A FAO as sufficient to protect against tissue injury, showing tubular Cpt1a gain-of-function restores oxidative metabolism and suppresses renal fibrosis across three models.","evidence":"Conditional transgenic knock-in mouse, three fibrosis models, palmitate oxidation and ATP assays","pmids":["33465052"],"confidence":"High","gaps":["Sufficiency shown by overexpression; loss-of-function necessity addressed separately and later contested"]},{"year":2021,"claim":"Defined a systemic CPT1A function by showing hepatic Cpt1a loss activates the PPARα–FGF21 axis to drive adipose browning, establishing liver–adipose metabolic crosstalk.","evidence":"Liver-specific knockout, RNAseq, anti-FGF21 neutralization, metabolic phenotyping","pmids":["34675003"],"confidence":"High","gaps":["Mechanism linking hepatic FAO loss to PPARα-FGF21 induction not fully resolved"]},{"year":2022,"claim":"Identified protein-stability control of CPT1A, linking mitochondrial STAT3/NF-κB to USP50-mediated deubiquitination that sustains FAO during sepsis.","evidence":"MS, reciprocal Co-IP, ChIP at USP50 promoter, knockdown, knock-in mouse","pmids":["34976224"],"confidence":"High","gaps":["E3 ligase opposing USP50 not identified","Direct CPT1A ubiquitination sites not mapped"]},{"year":2022,"claim":"Extended CPT1A FAO into innate immunity and cell behavior, showing it is required for neutrophil chemotaxis and drives clathrin expression for osteoclast fusion via C/EBPβ.","evidence":"Pharmacologic inhibition in pneumonia model; ChIP at CLTA/CLTC promoters and fusion assays","pmids":["36513703","35273614"],"confidence":"Medium","gaps":["Chemotaxis effect relies on pharmacology rather than genetics","C/EBPβ link is single-lab"]},{"year":2023,"claim":"Uncovered a scaffolding function in innate immune signaling, showing CPT1A recruits ZDHHC4 to palmitoylate MAVS at Cys79, shifting ubiquitination to stabilize MAVS and amplify type I interferon.","evidence":"Multiple Co-IPs, palmitoylation assays, MAVS Cys79 mutagenesis, K48/K63 ubiquitination analysis, in vivo tumor models","pmids":["38016475"],"confidence":"High","gaps":["How CPT1A bridges mitochondrial and ER-localized ZDHHC4 spatially is unclear"]},{"year":2023,"claim":"Defined CPT1A as a direct apoptosis and mitophagy regulator, anchoring Bcl-2 via its BH3 domain and modulating the PHB2–PARL interaction to promote PINK1/Parkin mitophagy.","evidence":"Co-IP, activity inhibition, macrophage-specific Bcl-2 deletion, fibrosis model; PHB2 Co-IP with M593S gain-of-function mutant in db/db cardiomyopathy","pmids":["34413485","37042471"],"confidence":"High","gaps":["Bcl-2 anchoring data are High-confidence; PHB2/mitophagy axis is single-lab Medium","Whether catalytic activity and scaffolding are separable not fully resolved"]},{"year":2023,"claim":"Showed CPT1A FAO confers immune evasion and stemness across cancers, sustaining prosurvival signaling against CTL/CAR-T killing and feeding β-catenin and VEGFR3 epigenetic programs through acetyl-CoA.","evidence":"CPT1A knockout, IFN-γ/AMPK manipulation, co-culture cytotoxicity, CAR-T tumor models; acetyl-CoA and H3K9ac analyses with acetate rescue","pmids":["37722058","32913185","29940537"],"confidence":"High","gaps":["Cancer-context dependence of these effects not generalized","Multiple downstream readouts from single labs"]},{"year":2024,"claim":"Challenged the necessity of mitochondrial CPT1A FAO in kidney, showing tubular knockout is dispensable due to compensatory peroxisomal β-oxidation, contrasting with earlier sufficiency claims.","evidence":"Tubule-specific knockout, multiple injury models, 2-year aging, snRNA-seq, palmitate oxidation assays","pmids":["38516886"],"confidence":"High","gaps":["Extent of peroxisomal compensation in other tissues unknown"]},{"year":2024,"claim":"Expanded CPT1A's post-translational and post-transcriptional regulatory network, defining m6A/IGF2BP1/ALKBH5 control of CPT1A mRNA stability and reciprocal c-Myc and ferroptosis-suppressing axes.","evidence":"Me-RIP, mRNA stability assays, Co-IP, ubiquitination assays, knockout mice across cancer and macrophage models","pmids":["38479704","39734009","38453925"],"confidence":"Medium","gaps":["Feedback loops supported with limited step-by-step mutagenesis","Each axis is single-lab"]},{"year":2025,"claim":"Consolidated CPT1A as a multifunctional succinyltransferase, showing MFF succinylation drives membrane-contact-site formation and SREBP1/SCD1 lipid desaturation for cancer stemness.","evidence":"Co-IP, succinylation assays, SREBP1/SCD1 analysis, Glyburide LSTase inhibition, stemness assays","pmids":["39956875"],"confidence":"Medium","gaps":["Catalytic mechanism and substrate selectivity of LSTase activity remain undefined","Single lab"]},{"year":null,"claim":"It remains unresolved how a single protein partitions between its acyltransferase, succinyltransferase, scaffolding, and trafficking activities, and whether these are structurally separable or competing functions in the same molecule.","evidence":"No discovery in the corpus reconstitutes or structurally separates the distinct CPT1A activities","pmids":[],"confidence":"Low","gaps":["No structure capturing CPT1A in its various functional states","No mutant that selectively abolishes succinyltransferase while preserving FAO","Tissue-specific dominance of each function unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[19,4,26,38,33]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,13]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,11,13,22]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,0,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,27,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,14,25]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,21,32]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,38]}],"complexes":["CPT1A-ACSL-VDAC outer membrane complex"],"partners":["VDAC1","RAB14","S100A10","BCL-2","PHB2","ZDHHC4","ATG16L1","C-MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50416","full_name":"Carnitine O-palmitoyltransferase 1, liver isoform","aliases":["Carnitine O-palmitoyltransferase I, liver isoform","CPT I","CPTI-L","Carnitine palmitoyltransferase 1A","Succinyltransferase CPT1A"],"length_aa":773,"mass_kda":88.4,"function":"Catalyzes the transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion (PubMed:11350182, PubMed:14517221, PubMed:16651524, PubMed:9691089). Also possesses a lysine succinyltransferase activity that can regulate enzymatic activity of substrate proteins such as ENO1 and metabolism independent of its classical carnitine O-palmitoyltransferase activity (PubMed:29425493). Plays an important role in hepatic triglyceride metabolism (By similarity). Also plays a role in inducible regulatory T-cell (iTreg) differentiation once activated by butyryl-CoA that antagonizes malonyl-CoA-mediated CPT1A repression (By similarity). Sustains the IFN-I response by recruiting ZDHCC4 to palmitoylate MAVS at the mitochondria leading to MAVS stabilization and activation (PubMed:38016475). Promotes ROS-induced oxidative stress in liver injury via modulation of NFE2L2 and NLRP3-mediated signaling pathways (By similarity)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/P50416/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPT1A","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPT1A","total_profiled":1310},"omim":[{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612795","title":"POLYUNSATURATED FATTY ACIDS PLASMA LEVEL QUANTITATIVE TRAIT LOCUS 1; PUFAQTL1","url":"https://www.omim.org/entry/612795"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"},{"mim_id":"608846","title":"CARNITINE PALMITOYLTRANSFERASE IC; CPT1C","url":"https://www.omim.org/entry/608846"},{"mim_id":"605353","title":"GHRELIN; GHRL","url":"https://www.omim.org/entry/605353"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CPT1A"},"hgnc":{"alias_symbol":["CPT1-L","L-CPT1"],"prev_symbol":["CPT1"]},"alphafold":{"accession":"P50416","domains":[{"cath_id":"-","chopping":"1-48","consensus_level":"high","plddt":57.7008,"start":1,"end":48},{"cath_id":"-","chopping":"56-128_152-157","consensus_level":"high","plddt":88.1695,"start":56,"end":157},{"cath_id":"3.30.559.10","chopping":"181-238_545-763","consensus_level":"medium","plddt":95.8666,"start":181,"end":763},{"cath_id":"3.30.559.70","chopping":"263-542","consensus_level":"high","plddt":96.791,"start":263,"end":542}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50416","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50416-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50416-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPT1A","jax_strain_url":"https://www.jax.org/strain/search?query=CPT1A"},"sequence":{"accession":"P50416","fasta_url":"https://rest.uniprot.org/uniprotkb/P50416.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50416/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50416"}},"corpus_meta":[{"pmid":"31900483","id":"PMC_31900483","title":"CPT1A-mediated 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This complex is proposed to transfer activated fatty acids through the outer mitochondrial membrane.\",\n      \"method\": \"Blue native PAGE, immunoblotting, mass spectrometry, co-immunoprecipitation with antisera against each protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, blue native PAGE, and MS all converge on the same complex in a single rigorous study\",\n      \"pmids\": [\"21622568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PPARα activates CPT1A transcription through a binding site in the second intron of the rat CPT1A gene, while PGC-1α activates CPT1A through a separate element in the first intron; these two regulators act via independent gene elements and do not cooperate through each other's binding sites.\",\n      \"method\": \"Luciferase reporter assays, PPARα binding site mutation, WY14643 ligand treatment, PGC-1α shRNA knockdown, in vivo fasted rat liver transfection\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific intronic elements, in vitro and in vivo reporter assays, shRNA knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"20638986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPT1A interacts with Rab14, and this interaction facilitates fatty acid trafficking from lipid droplets to mitochondria in NPC cells, thereby reducing radiation-induced lipid accumulation and maximizing ATP production to promote radiation resistance.\",\n      \"method\": \"LC-MS/MS protein identification, co-immunoprecipitation, immunofluorescence, in situ proximity ligation assay, computational docking, pulse-chase fatty acid trafficking assay with BODIPY C16 and MitoTracker Red, Rab14 knockdown\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, proximity ligation, functional rescue with multiple orthogonal methods in one study\",\n      \"pmids\": [\"29721083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Butyrate is converted by ACSS2 to butyryl-CoA (BCoA), which antagonizes the binding of malonyl-CoA at Arg243 of CPT1A, thereby upregulating CPT1A activity and promoting fatty acid oxidation and iTreg differentiation. Mutation of CPT1A Arg243 impairs both malonyl-CoA and butyryl-CoA binding, identifying this residue as the responsible site.\",\n      \"method\": \"In vitro CPT1A activity assays, site-directed mutagenesis of Arg243, ACSS2 inhibitor, iTreg differentiation assays, mouse colitis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with enzymatic activity assay, pharmacologic inhibition, and in vivo functional validation\",\n      \"pmids\": [\"34035164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CPT1A functions as a lysine succinyltransferase (LSTase), interacting with S100A10 and succinylating it at Lys47, which stabilizes S100A10 by suppressing ubiquitylation and proteasomal degradation, thereby promoting gastric cancer cell invasion and migration. Desuccinylation is mediated by SIRT5.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry identification of succinylation site, succinylation mimetic mutant (K47E) overexpression, cell invasion/migration assays, knockdown experiments\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS identification of PTM, functional mutant, single lab\",\n      \"pmids\": [\"30394687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mitochondrial STAT3 stabilizes CPT1A protein by abrogating its ubiquitination and degradation in LPS-treated macrophages. This stabilization is mediated through CPT1A interaction with ubiquitin-specific peptidase 50 (USP50), whose promoter is bound by NF-κB (downstream of mitochondrial STAT3), thereby linking mitochondrial STAT3 to FAO-dependent metabolic reprogramming in sepsis.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation (CPT1A–USP50 interaction), ChIP assay (NF-κB at USP50 promoter), USP50 knockdown, metabolic assays, knock-in mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic knockdown, knock-in mouse, multiple orthogonal methods\",\n      \"pmids\": [\"34976224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A recruits the ER-localized palmitoyltransferase ZDHHC4 to catalyze MAVS palmitoylation at Cys79, which promotes MAVS stabilization and activation by inhibiting K48-linked ubiquitination while facilitating K63-linked ubiquitination, thereby amplifying the type I interferon response. This is a non-FAO enzymatic function of CPT1A.\",\n      \"method\": \"Co-immunoprecipitation (CPT1A–ZDHHC4 and CPT1A–MAVS), palmitoylation assays, mutagenesis of MAVS Cys79, ubiquitination assays (K48 vs K63), genetic overexpression/depletion, in vivo tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of palmitoylation pathway with mutagenesis, multiple Co-IPs, ubiquitination characterization, and in vivo validation in one rigorous study\",\n      \"pmids\": [\"38016475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CPT1A-dependent fatty acid oxidation promotes β-catenin acetylation and nuclear translocation in colon cancer cells exposed to adipocytes or fatty acids, activating Wnt/β-catenin target genes associated with cancer stemness.\",\n      \"method\": \"CPT1A siRNA knockdown, β-catenin nuclear translocation assays, p300 inhibitor rescue, 3D organoid culture, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with defined pathway readout, pharmacologic rescue with p300 inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"32913185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPT1A overexpression in prostate cancer cells increases histone acetylation by supplying acetyl groups, supporting castration-resistant growth; this histone acetylation increase is partially reversed by a p300-specific inhibitor, indicating a link between lipid catabolism and epigenetic regulation.\",\n      \"method\": \"CPT1A overexpression and knockdown cell lines, histone acetylation analysis, p300 inhibitor treatment, androgen deprivation experiments, tumor growth assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic OE/KD with defined epigenetic readout and pharmacologic rescue, single lab\",\n      \"pmids\": [\"31547059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cpt1a overexpression in renal tubular epithelial cells (TECs) restores oxidative metabolism and mitochondrial number, increases palmitate oxidation and ATP levels, reduces fibrotic marker expression and macrophage influx in three mouse models of renal fibrosis, establishing that gain-of-function in CPT1A-mediated FAO is sufficient to protect against fibrosis.\",\n      \"method\": \"Conditional transgenic CPT1A knock-in mouse, three fibrosis models (UUO, FAN, adenine nephrotoxicity), palmitate oxidation assays, ATP measurements, histology, gene expression\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional transgenic model replicated across three independent injury models with biochemical readouts\",\n      \"pmids\": [\"33465052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A-dependent FAO in cancer cells is induced by T cell-derived IFN-γ in an AMPK-dependent manner and confers resistance to cytotoxic T lymphocyte killing by maintaining prosurvival signaling. Genetic repression or pharmacologic inhibition of CPT1A renders tumors more susceptible to CAR-T cell therapy.\",\n      \"method\": \"CPT1A knockout and knockdown, IFN-γ treatment, AMPK inhibition, co-culture cytotoxicity assays, CAR-T cell therapy in tumor-bearing mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, defined upstream signal (IFN-γ/AMPK), in vitro and in vivo functional readouts\",\n      \"pmids\": [\"37722058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A directly binds PHB2 in the mitochondria and modulates the PHB2-PARL interaction; increased CPT1A activity (induced by L-carnitine or amino acid mutation M593S) enhances the PHB2-PARL interaction and thereby promotes PINK1-Parkin-dependent mitophagy, improving mitochondrial function in diabetic cardiomyopathy.\",\n      \"method\": \"Co-immunoprecipitation (CPT1A–PHB2), adenovirus-mediated overexpression of WT and M593S mutant CPT1A, PARL overexpression rescue, immunofluorescence, transmission electron microscopy, db/db mouse model\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, gain-of-function mutant, rescue experiments, in vivo model, single lab\",\n      \"pmids\": [\"37042471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatocyte-specific Cpt1a knockout in mice activates the PPARα-FGF21 axis, elevating circulating FGF21, which drives adipose browning and increased energy expenditure; antibody-mediated FGF21 neutralization abolishes these effects, establishing a CPT1A-mediated liver-adipose cross-talk pathway.\",\n      \"method\": \"Liver-specific Cpt1a knockout mice, RNAseq, anti-FGF21 antibody neutralization, metabolic phenotyping, adipose tissue analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, RNAseq pathway identification, antibody rescue confirming FGF21 mediates the phenotype\",\n      \"pmids\": [\"34675003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A directly interacts with Bcl-2 at its BH3 domain, anchoring Bcl-2 in the mitochondria in an activity-dependent manner to attenuate apoptosis in lung macrophages; disruption of this interaction induces apoptosis and reduces pulmonary fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, CPT1A activity inhibition, Bcl-2 macrophage-specific deletion, bleomycin fibrosis mouse model, ABT-199 pharmacologic inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying BH3 domain interaction, activity-dependence demonstrated, genetic and pharmacologic validation in vivo\",\n      \"pmids\": [\"34413485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ethanol induces repressive H3K9 deacetylation at the CPT1A promoter via HDAC1 recruitment mediated by SP1 (proximal region) and HNF4α (distal region); butyrate/tributyrin inhibits HDAC1 and facilitates p300 binding at these same sites, restoring CPT1A transcription and reducing hepatic steatosis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in vivo (mouse liver) and in vitro (primary hepatocytes), ethanol and butyrate treatment, histone modification analysis\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP identifying specific HDAC1 and HAT binding at CPT1A promoter, validated in vivo and in vitro with mechanistic resolution of proximal/distal elements\",\n      \"pmids\": [\"31654770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT1 directly deacetylates CPT1A at Lys675, which suppresses ubiquitin-dependent degradation of CPT1A and promotes FAO; berberine increases SIRT1 expression, which in turn increases CPT1A protein level and activity to alleviate NAFLD.\",\n      \"method\": \"Co-immunoprecipitation (SIRT1–CPT1A) in HEK293T cells, CPT1A activity assay, site identification at Lys675, SIRT1 overexpression/knockdown\",\n      \"journal\": \"Gastroenterology report\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying interaction, site-level PTM characterization, functional assays, single lab\",\n      \"pmids\": [\"37293270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"High-fructose feeding induces hypermethylation of the CPT1A promoter region, associated with reduced CPT1A mRNA expression and hepatic lipid accumulation in rats.\",\n      \"method\": \"qAMP restriction digestion and real-time PCR methylation analysis, real-time PCR for mRNA quantification, rat dietary model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single epigenetic readout method (qAMP) in a single dietary model, no mechanistic dissection of the methylation writers/erasers\",\n      \"pmids\": [\"26519879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"High-fat diet elevates hepatic Cpt1a expression through coordinated epigenetic mechanisms: reduced DNA methylation and increased H3K4Me2 upstream/within the promoter, accompanied by increased PPARα, C/EBPβ, PGC-1α, and BAF60a (SMARCD1) binding in the first intron at the transcription start site region.\",\n      \"method\": \"Bisulfite sequencing (DNA methylation), ChIP (H3K4Me2, PPARα, C/EBPβ, PGC-1α, BAF60a), rat dietary model, NEFA-treated H4IIEC3 hepatoma cells\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and methylation analysis with multiple histone and transcription factor targets, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"30605728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Liver-targeted AAV delivery of a permanently active mutant form of human CPT1A (hCPT1AM) enhances hepatic FAO and autophagy, reduces liver steatosis, and improves glucose homeostasis in a mouse model of established obesity and NAFLD.\",\n      \"method\": \"AAV9-hCPT1AM gene delivery, FAO assays, lipidomic analysis, metabolic phenotyping in HFD mice\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function gene therapy with biochemical readouts in vivo, single lab\",\n      \"pmids\": [\"32666604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CPT1A catalyzes the rate-limiting step of long-chain fatty acid oxidation: transfer of long-chain acyl groups from acyl-CoA to carnitine, generating acylcarnitines that cross the inner mitochondrial membrane. The enzyme is inhibited allosterically by malonyl-CoA.\",\n      \"method\": \"Review synthesizing enzymatic activity assays and biochemical studies (multiple prior studies summarized in review context)\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic function established by decades of in vitro enzymatic assays and mutational studies across multiple labs, confirmed in this comprehensive review\",\n      \"pmids\": [\"31900483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic deletion of Cpt1a specifically in T cells demonstrates that the ACC2/Cpt1a axis is largely dispensable for effector, memory, and regulatory T cell formation, and that the effects of etomoxir on T cell differentiation are independent of Cpt1a expression.\",\n      \"method\": \"T cell-specific Cpt1a genetic knockout mice, primary/memory/regulatory T cell functional assays, etomoxir treatment comparison\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with multiple T cell subset readouts; negative finding robustly established by genetic model\",\n      \"pmids\": [\"30043753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1A restrains ubiquitination and degradation of c-Myc, while c-Myc transcriptionally activates CPT1A expression, forming a positive feedback loop that activates the NRF2/GPX4 antioxidant system and downregulates ACSL4, thereby suppressing ferroptosis in lung cancer stem cells.\",\n      \"method\": \"Lung epithelial-specific Cpt1a-knockout mouse model, metabolomics, transcriptomics, co-immunoprecipitation (CPT1A–c-Myc), ubiquitination assays, NRF2/GPX4/ACSL4 expression analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic KO mouse, pathway analysis; feedback loop supported but with limited direct mutagenesis to dissect each step\",\n      \"pmids\": [\"38453925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel covalent inhibitor DHP-B binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 protein interaction, leading to increased mitochondrial permeability and reduced oxygen consumption in colorectal cancer cells.\",\n      \"method\": \"Covalent binding characterization, Cys96 identification, CPT1A-VDAC1 co-immunoprecipitation, oxygen consumption assay, mitochondrial permeability measurement, in vitro and in vivo tumor models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — covalent inhibitor site identification, Co-IP for CPT1A-VDAC1 interaction, functional assays, single lab\",\n      \"pmids\": [\"37977042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPT1A-mediated FAO in osteoclast precursors promotes their fusion by increasing expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) through enhanced binding of transcription factor C/EBPβ to CLTA and CLTC promoters, thereby driving clathrin-dependent endocytosis and podosome formation.\",\n      \"method\": \"CPT1A overexpression/knockdown, C/EBPβ ChIP at CLTA/CLTC promoters, clathrin expression analysis, osteoclast fusion and podosome assays, RA patient samples\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP linking FAO to transcription factor binding, genetic manipulation, defined cellular phenotype, single lab\",\n      \"pmids\": [\"35273614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A loss reduces acetyl-CoA production, which decreases histone acetylation and epigenetically reprograms BCAA catabolism, leading to BCAA accumulation and hyperactivation of mTOR signaling in TP53-mutant hepatocellular carcinoma; this renders cells sensitive to the mTOR inhibitor AZD-8055.\",\n      \"method\": \"CPT1A genetic ablation (de novo liver tumor and xenograft models), acetyl-CoA measurement, histone acetylation analysis, BCAA metabolomics, mTOR pathway analysis, mTOR inhibitor treatment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics, histone acetylation measurements, genetic ablation, pathway epistasis, single lab\",\n      \"pmids\": [\"38823763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXA1 transcriptionally promotes CPT1A expression by binding a cis-inducible element in the CPT1A promoter, as demonstrated by ChIP and dual-luciferase reporter assays; FOXA1-mediated CPT1A upregulation promotes FAO and alleviates ferroptosis in renal tubular epithelial cells under diabetic conditions.\",\n      \"method\": \"Chromatin immunoprecipitation assay, dual-luciferase reporter gene assay, FOXA1 overexpression/knockdown, CPT1A activity and FAO assays, diabetic mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and luciferase reporter directly demonstrating FOXA1 binding to CPT1A promoter, functional validation, single lab\",\n      \"pmids\": [\"38128823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CPT1A uses its lysine succinyltransferase (LSTase) activity to succinylate mitochondrial fission factor (MFF), which promotes mitochondria-associated membrane formation and SREBP1 activation, leading to SCD1 upregulation and lipid desaturation essential for ovarian cancer stem cell stemness maintenance.\",\n      \"method\": \"Co-immunoprecipitation (CPT1A–MFF), succinylation assays, SREBP1 activation assays, SCD1 expression analysis, LSTase activity inhibition with Glyburide, in vitro and in vivo stemness assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PTM assays, pharmacologic LSTase inhibition, functional stemness readout, single lab\",\n      \"pmids\": [\"39956875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cpt1a-dependent mitochondrial fatty acid oxidation is required for neutrophil chemotaxis; pharmacologic inhibition of Cpt1a impairs chemoattractant signal amplification, blunts neutrophil trafficking to sites of infection, and increases susceptibility to bacterial pneumonia in mice.\",\n      \"method\": \"Pharmacologic Cpt1a inhibition in murine pneumonia model, neutrophil chemotaxis assays, human phenome association study for pneumonia risk variant\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic inhibition with defined cellular phenotype (chemotaxis), in vivo infection model, human genetic association corroboration\",\n      \"pmids\": [\"36513703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A in AgRP neurons is required for sex-dependent regulation of food intake, energy expenditure, and fluid balance; male Cpt1aKO mice show altered food intake while female Cpt1aKO mice show increased energy expenditure and brown adipose tissue activity; both sexes develop polydipsia and polyuria with reduced vasopressin levels. AgRP neurons from Cpt1aKO mice show reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus.\",\n      \"method\": \"AgRP neuron-specific Cpt1a knockout (tamoxifen-inducible AgRPCreERT2), metabolic phenotyping, calorimetry, AAV-mediated neuronal labeling, RiboTag ribosome profiling, single-nucleus RNA-seq\",\n      \"journal\": \"Biology of sex differences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with comprehensive metabolic, neuroanatomical, and molecular phenotyping\",\n      \"pmids\": [\"36966335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tubule-specific Cpt1a deletion in mice does not significantly affect kidney function or fibrosis after aging or chronic injury; primary tubule cells lacking Cpt1a show modest reduction in palmitate oxidation but compensate through upregulation of peroxisomal FAO enzymes, suggesting peroxisomal β-oxidation compensates for loss of mitochondrial CPT1A-mediated FAO in tubules.\",\n      \"method\": \"Tubule-specific Cpt1a conditional KO mice, aristolochic acid and UUO injury models, 2-year aging, single-nuclear RNA-Seq, palmitate oxidation assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple injury models and aging, snRNA-Seq, biochemical oxidation assays; well-controlled negative/compensatory finding\",\n      \"pmids\": [\"38516886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALKBH5 demethylase removes m6A modification from CPT1A mRNA, enhancing its stability and upregulating CPT1A expression in macrophages, which promotes M2 macrophage polarization and FAO, facilitating colorectal cancer progression.\",\n      \"method\": \"Me-RIP assay, Actinomycin D mRNA stability assay, ALKBH5 gain-of-function, OCR measurement, co-culture CRC/macrophage model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Me-RIP and mRNA stability assays directly demonstrating m6A regulation of CPT1A mRNA, functional assays, single lab\",\n      \"pmids\": [\"38479704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1A promotes K63-type ubiquitination of IGF2BP1 via RNF5; IGF2BP1 then binds m6A sites on CPT1A mRNA and enhances its stability, creating a regulatory axis (PPARγ-RNF5-IGF2BP1-CPT1A) in steatotic hepatocellular carcinoma that sustains FAO.\",\n      \"method\": \"RNF5–IGF2BP1 interaction assays, K63-ubiquitination characterization, m6A-RIP for CPT1A mRNA, mRNA stability assays, PPARγ ChIP at RNF5 promoter, lipidomics, transcriptomics\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP/ubiquitination assays, m6A-RIP, ChIP for upstream regulation; single lab but orthogonal methods\",\n      \"pmids\": [\"39734009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PACS2 positively regulates CPT1A expression; PACS2 silencing downregulates CPT1A and upregulates DHODH, reversing HGPA-induced ferroptosis in cardiomyocytes. CPT1A agonist treatment in PACS2-silenced cells re-exacerbates ferroptosis and mitochondrial damage, placing CPT1A downstream of PACS2 in the PACS2/CPT1A/DHODH ferroptosis signaling pathway.\",\n      \"method\": \"PACS2 siRNA knockdown, CPT1A agonist rescue, ferroptosis markers (iron, lipid peroxides, ROS), STZ/HFD diabetic mouse model, cardiac function measurement\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with pharmacologic rescue establishing pathway order, in vivo mouse model, single lab\",\n      \"pmids\": [\"39633391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Astragaloside IV (ASIV) restores CPT1A activity, which in turn mediates K99 succinylation of HSD17B10; this succinylation maintains mitochondrial RNase P stability by stabilizing the HSD17B10-MRPP1 interaction. K99R mutation of HSD17B10 disrupts its binding to CPT1A and MRPP1, impairs RNase P activity, and induces oxidative stress. Molecular docking and cell thermal shift assay suggest ASIV directly binds CPT1A.\",\n      \"method\": \"Succinylated proteomics, site-directed mutagenesis (K99R), molecular docking, cell thermal shift assay, Co-IP (HSD17B10–CPT1A, HSD17B10–MRPP1), RNase P activity assay, db/db mouse model\",\n      \"journal\": \"Phytotherapy research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM proteomics, site mutagenesis, Co-IP, thermal shift; single lab\",\n      \"pmids\": [\"39038923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1A anchors Bcl2 to the mitochondrial membrane in podocytes, preventing cytochrome C release and mitochondrial apoptosis; CPT1A also fosters lipid consumption via FAO, reducing lipotoxicity. FOXA1 is identified as a transcription factor for CPT1A in podocytes. CPT1A overexpression protects against albuminuria and glomerulosclerosis in diabetic mice.\",\n      \"method\": \"CPT1A overexpression, streptozotocin diabetic mouse model, Bcl2 mitochondrial localization assay, cytochrome C release assay, FOXA1 identification as upstream regulator\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in vivo with defined molecular mechanisms (Bcl2 anchoring, FOXA1 regulation), single lab\",\n      \"pmids\": [\"38506804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A novel homozygous missense mutation R595W in CPT1A reduces CPT1A enzymatic activity by inducing steric hindrance: Arg595 contributes to a hydrogen-bond network with Cys304 and Met593, and its replacement by tryptophan causes steric clash with Ile480 in α-helix 12, disrupting protein architecture and function without directly affecting the catalytic site or carnitine pocket.\",\n      \"method\": \"CPT1A activity assay in patient fibroblasts, sequence alignment, protein structural modeling, comparison with known C304W mutant mechanism\",\n      \"journal\": \"JIMD reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic activity measurement in patient cells combined with structural modeling; mechanistic insight from modeling without crystal structure\",\n      \"pmids\": [\"23430932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CPT1A-mediated FAO promotes VEGF-C and VEGF-D expression in breast cancer cells and regulates VEGFR3 expression in lymphatic endothelial cells via acetyl-CoA-mediated H3K9 acetylation, promoting lymphangiogenesis; acetate supplementation rescues VEGFR3 expression upon CPT1A knockdown.\",\n      \"method\": \"CPT1A shRNA knockdown, LC-MS acetyl-CoA/CoA ratio measurement, VEGF-C/D and VEGFR3 expression analysis, H3K9ac analysis, acetate rescue, transwell and lymphatic vessel formation assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolite measurement (acetyl-CoA), epigenetic readout (H3K9ac), and acetate rescue connecting FAO to histone modification and VEGFR3; single lab\",\n      \"pmids\": [\"29940537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Coriobacteriaceae bacteria (Cori.ST1911) activate CPT1A and increase acylcarnitine levels in colorectal cancer cells via the CPT1A-ERK signaling pathway, promoting tumorigenesis; this was demonstrated in CRC cell lines, organoids, and multiple CRC mouse models.\",\n      \"method\": \"16S rRNA and metagenomic sequencing, LC-MS/MS metabolomics, CRC cell/organoid co-culture with Coriobacteriaceae, CPT1A-ERK pathway analysis, multiple CRC mouse models\",\n      \"journal\": \"NPJ biofilms and microbiomes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway analysis in multiple model systems with metabolomic validation; single lab\",\n      \"pmids\": [\"38245554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1A mediates chemoresistance in hypopharyngeal squamous cell carcinoma by interacting with autophagy-related protein ATG16L1 and stimulating its succinylation, which drives autophagosome formation and autophagy; 3-methyladenine (autophagy inhibitor) or CPT1A inhibitor reduces cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation (CPT1A–ATG16L1), succinylation assays, 3-MA autophagy inhibitor treatment, CPT1A inhibitor treatment, in vitro and in vivo cisplatin sensitivity assays\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, succinylation characterization, pharmacologic rescue; single lab\",\n      \"pmids\": [\"37961047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAT3/CPT1A-dependent FAO sustains hepatic stellate cell (HSC) proliferation and activation; cryptotanshinone inhibits STAT3 phosphorylation and nuclear translocation, reducing CPT1A expression and FAO (measured by ATP and acetyl-CoA reduction), with CPT1A overexpression reversing the anti-fibrotic effect.\",\n      \"method\": \"Transcriptomic sequencing, CPT1A and CPT1B expression analysis, STAT3 phosphorylation and nuclear translocation assay, ATP and acetyl-CoA measurement, CPT1A overexpression rescue, CCl4 mouse fibrosis model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by pharmacologic inhibition and genetic rescue, metabolite measurement; single lab\",\n      \"pmids\": [\"38936533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPT1A is the rate-limiting outer mitochondrial membrane enzyme that transfers long-chain acyl groups from acyl-CoA to carnitine (generating acylcarnitines for inner-membrane transport), is allosterically inhibited by malonyl-CoA at Arg243, forms a complex with ACSL and VDAC in the outer membrane to channel activated fatty acids, and also possesses a lysine succinyltransferase activity that post-translationally modifies substrates (S100A10, MFF, ATG16L1, HSD17B10); its transcription is independently activated by PPARα (second intron) and PGC-1α (first intron), regulated epigenetically by HDAC1/SIRT1 and DNA methylation, and its protein stability is controlled by USP50-mediated deubiquitination (downstream of mitochondrial STAT3/NF-κB) and SIRT1-mediated deacetylation at Lys675, while non-canonically it recruits ZDHHC4 to palmitoylate MAVS at Cys79, stabilizing innate immune signaling, and interacts with Bcl-2 (BH3 domain), Rab14, PHB2, VDAC1, c-Myc, and ATG16L1 to regulate apoptosis, fatty acid trafficking, mitophagy, and autophagy across multiple cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPT1A is the rate-limiting outer mitochondrial membrane enzyme of long-chain fatty acid oxidation (FAO), transferring long-chain acyl groups from acyl-CoA to carnitine to generate acylcarnitines for inner-membrane import, and is allosterically inhibited by malonyl-CoA [#19]. It does not act alone in the membrane: it assembles into a complex with long-chain acyl-CoA synthetase (ACSL) and the channel VDAC that funnels activated fatty acids through the outer membrane [#0], and the CPT1A–VDAC1 interaction is itself required for normal mitochondrial permeability and respiration [#22]. Malonyl-CoA sensitivity and catalysis converge on defined residues—malonyl-CoA and the antagonist butyryl-CoA both bind Arg243 [#3], a covalent inhibitor engages Cys96 [#22], and a disease-causing R595W substitution disrupts protein architecture remote from the catalytic pocket [#35]. Beyond its catalytic role, CPT1A is a moonlighting protein: it possesses lysine succinyltransferase activity that modifies and stabilizes diverse substrates including S100A10, mitochondrial fission factor MFF, ATG16L1, and HSD17B10 to influence migration, lipid desaturation, autophagy, and mitochondrial RNase P stability [#4, #26, #38, #33], and it serves as a scaffold that recruits ZDHHC4 to palmitoylate MAVS at Cys79, stabilizing innate immune signaling [#6]. CPT1A also anchors Bcl-2 at the mitochondria through its BH3 domain in an activity-dependent manner to restrain apoptosis [#13], and binds PHB2 to promote PINK1/Parkin-dependent mitophagy [#11]. Through the acetyl-CoA generated by FAO, CPT1A links lipid catabolism to epigenetic regulation, supplying acetyl groups for histone acetylation and Wnt/β-catenin and VEGFR3 signaling [#7, #8, #36]. CPT1A expression is transcriptionally driven by PPARα and PGC-1α through independent intronic elements [#1] and by FOXA1 [#25], controlled epigenetically via HDAC1/p300 and DNA methylation [#14], and its protein stability is governed by USP50-mediated deubiquitination downstream of mitochondrial STAT3/NF-κB [#5] and SIRT1-mediated deacetylation at Lys675 [#15]. Physiologically, CPT1A-mediated FAO mediates liver–adipose crosstalk via the PPARα–FGF21 axis [#12], regulates AgRP-neuron control of feeding and energy balance [#28], drives neutrophil chemotaxis [#27], and is protective in renal and cardiac disease models [#9, #34], though tissue-specific knockouts reveal substantial functional redundancy with peroxisomal β-oxidation in kidney tubules and dispensability in T cells [#29, #20].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established CPT1A as the rate-limiting, malonyl-CoA-inhibited enzyme that commits long-chain fatty acids to mitochondrial oxidation, defining the baseline catalytic function on which all later work builds.\",\n      \"evidence\": \"Synthesis of enzymatic activity and biochemical studies in a comprehensive review\",\n      \"pmids\": [\"31900483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve residue-level determinants of malonyl-CoA sensitivity or catalysis\", \"Review context rather than a single new experiment\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how CPT1A transcription is controlled, showing PPARα and PGC-1α act through separate, non-cooperating intronic elements rather than a single regulatory module.\",\n      \"evidence\": \"Luciferase reporters, intronic element mutagenesis, ligand treatment, shRNA, and in vivo rat liver transfection\",\n      \"pmids\": [\"20638986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein-level or epigenetic regulation\", \"Defined in rat gene; human element conservation not tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CPT1A is not an isolated enzyme but a member of an outer-membrane ACSL–VDAC complex, providing a structural basis for channeling activated fatty acids across the membrane.\",\n      \"evidence\": \"Blue native PAGE, MS, and reciprocal Co-IP from liver mitochondria\",\n      \"pmids\": [\"21622568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the complex not determined\", \"Functional channeling proposed but not directly reconstituted\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked CPT1A to a Mendelian metabolic disorder by defining how a homozygous R595W substitution impairs enzyme activity through steric disruption rather than catalytic-site loss.\",\n      \"evidence\": \"Activity assay in patient fibroblasts plus structural modeling\",\n      \"pmids\": [\"23430932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure to confirm modeled steric clash\", \"Single patient genotype\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed the first moonlighting enzymatic function of CPT1A—lysine succinyltransferase activity—by showing it succinylates and stabilizes S100A10 to promote cancer cell invasion.\",\n      \"evidence\": \"Co-IP, MS site identification, succinyl-mimetic mutant, invasion assays, SIRT5 desuccinylation\",\n      \"pmids\": [\"30394687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; catalytic mechanism of succinyltransferase activity not dissected\", \"Relationship to the canonical acyltransferase active site unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a non-enzymatic trafficking role by showing CPT1A binds Rab14 to deliver fatty acids from lipid droplets to mitochondria, coupling lipid handling to radioresistance.\",\n      \"evidence\": \"LC-MS/MS, reciprocal Co-IP, proximity ligation, BODIPY-C16 pulse-chase, Rab14 knockdown\",\n      \"pmids\": [\"29721083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Generality beyond NPC cells untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tempered overinterpretation of FAO in immunity by genetically showing CPT1A is largely dispensable for T cell differentiation and that etomoxir effects are CPT1A-independent.\",\n      \"evidence\": \"T cell-specific Cpt1a knockout with multiple subset readouts and etomoxir comparison\",\n      \"pmids\": [\"30043753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not exclude roles in other immune cell types\", \"Compensatory pathways not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected CPT1A-derived acetyl-CoA to epigenetic reprogramming, showing FAO supplies acetyl groups for histone acetylation supporting castration-resistant prostate cancer growth.\",\n      \"evidence\": \"Overexpression/knockdown, histone acetylation analysis, p300 inhibitor rescue\",\n      \"pmids\": [\"31547059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct acetyl-CoA flux to histones not traced\", \"Specific histone loci not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established epigenetic control of CPT1A transcription, mapping HDAC1 recruitment via SP1/HNF4α and p300-mediated reversal by butyrate at defined promoter regions.\",\n      \"evidence\": \"In vivo and in vitro ChIP with ethanol and butyrate treatment\",\n      \"pmids\": [\"31654770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein-level regulation\", \"Studied in alcoholic steatosis context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided active-site resolution of CPT1A regulation by showing butyryl-CoA competes with malonyl-CoA at Arg243 to activate FAO and drive iTreg differentiation.\",\n      \"evidence\": \"In vitro activity assays, Arg243 mutagenesis, ACSS2 inhibition, iTreg and colitis models\",\n      \"pmids\": [\"34035164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dual-ligand binding at Arg243 not crystallographically resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CPT1A FAO as sufficient to protect against tissue injury, showing tubular Cpt1a gain-of-function restores oxidative metabolism and suppresses renal fibrosis across three models.\",\n      \"evidence\": \"Conditional transgenic knock-in mouse, three fibrosis models, palmitate oxidation and ATP assays\",\n      \"pmids\": [\"33465052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sufficiency shown by overexpression; loss-of-function necessity addressed separately and later contested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a systemic CPT1A function by showing hepatic Cpt1a loss activates the PPARα–FGF21 axis to drive adipose browning, establishing liver–adipose metabolic crosstalk.\",\n      \"evidence\": \"Liver-specific knockout, RNAseq, anti-FGF21 neutralization, metabolic phenotyping\",\n      \"pmids\": [\"34675003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking hepatic FAO loss to PPARα-FGF21 induction not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified protein-stability control of CPT1A, linking mitochondrial STAT3/NF-κB to USP50-mediated deubiquitination that sustains FAO during sepsis.\",\n      \"evidence\": \"MS, reciprocal Co-IP, ChIP at USP50 promoter, knockdown, knock-in mouse\",\n      \"pmids\": [\"34976224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase opposing USP50 not identified\", \"Direct CPT1A ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended CPT1A FAO into innate immunity and cell behavior, showing it is required for neutrophil chemotaxis and drives clathrin expression for osteoclast fusion via C/EBPβ.\",\n      \"evidence\": \"Pharmacologic inhibition in pneumonia model; ChIP at CLTA/CLTC promoters and fusion assays\",\n      \"pmids\": [\"36513703\", \"35273614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chemotaxis effect relies on pharmacology rather than genetics\", \"C/EBPβ link is single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a scaffolding function in innate immune signaling, showing CPT1A recruits ZDHHC4 to palmitoylate MAVS at Cys79, shifting ubiquitination to stabilize MAVS and amplify type I interferon.\",\n      \"evidence\": \"Multiple Co-IPs, palmitoylation assays, MAVS Cys79 mutagenesis, K48/K63 ubiquitination analysis, in vivo tumor models\",\n      \"pmids\": [\"38016475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CPT1A bridges mitochondrial and ER-localized ZDHHC4 spatially is unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CPT1A as a direct apoptosis and mitophagy regulator, anchoring Bcl-2 via its BH3 domain and modulating the PHB2–PARL interaction to promote PINK1/Parkin mitophagy.\",\n      \"evidence\": \"Co-IP, activity inhibition, macrophage-specific Bcl-2 deletion, fibrosis model; PHB2 Co-IP with M593S gain-of-function mutant in db/db cardiomyopathy\",\n      \"pmids\": [\"34413485\", \"37042471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bcl-2 anchoring data are High-confidence; PHB2/mitophagy axis is single-lab Medium\", \"Whether catalytic activity and scaffolding are separable not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed CPT1A FAO confers immune evasion and stemness across cancers, sustaining prosurvival signaling against CTL/CAR-T killing and feeding β-catenin and VEGFR3 epigenetic programs through acetyl-CoA.\",\n      \"evidence\": \"CPT1A knockout, IFN-γ/AMPK manipulation, co-culture cytotoxicity, CAR-T tumor models; acetyl-CoA and H3K9ac analyses with acetate rescue\",\n      \"pmids\": [\"37722058\", \"32913185\", \"29940537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cancer-context dependence of these effects not generalized\", \"Multiple downstream readouts from single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Challenged the necessity of mitochondrial CPT1A FAO in kidney, showing tubular knockout is dispensable due to compensatory peroxisomal β-oxidation, contrasting with earlier sufficiency claims.\",\n      \"evidence\": \"Tubule-specific knockout, multiple injury models, 2-year aging, snRNA-seq, palmitate oxidation assays\",\n      \"pmids\": [\"38516886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent of peroxisomal compensation in other tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded CPT1A's post-translational and post-transcriptional regulatory network, defining m6A/IGF2BP1/ALKBH5 control of CPT1A mRNA stability and reciprocal c-Myc and ferroptosis-suppressing axes.\",\n      \"evidence\": \"Me-RIP, mRNA stability assays, Co-IP, ubiquitination assays, knockout mice across cancer and macrophage models\",\n      \"pmids\": [\"38479704\", \"39734009\", \"38453925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Feedback loops supported with limited step-by-step mutagenesis\", \"Each axis is single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated CPT1A as a multifunctional succinyltransferase, showing MFF succinylation drives membrane-contact-site formation and SREBP1/SCD1 lipid desaturation for cancer stemness.\",\n      \"evidence\": \"Co-IP, succinylation assays, SREBP1/SCD1 analysis, Glyburide LSTase inhibition, stemness assays\",\n      \"pmids\": [\"39956875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic mechanism and substrate selectivity of LSTase activity remain undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single protein partitions between its acyltransferase, succinyltransferase, scaffolding, and trafficking activities, and whether these are structurally separable or competing functions in the same molecule.\",\n      \"evidence\": \"No discovery in the corpus reconstitutes or structurally separates the distinct CPT1A activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure capturing CPT1A in its various functional states\", \"No mutant that selectively abolishes succinyltransferase while preserving FAO\", \"Tissue-specific dominance of each function unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [19, 4, 26, 38, 33]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 11, 13, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 0, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 27, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 14, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 21, 32]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 38]}\n    ],\n    \"complexes\": [\n      \"CPT1A-ACSL-VDAC outer membrane complex\"\n    ],\n    \"partners\": [\n      \"VDAC1\",\n      \"Rab14\",\n      \"S100A10\",\n      \"Bcl-2\",\n      \"PHB2\",\n      \"ZDHHC4\",\n      \"ATG16L1\",\n      \"c-Myc\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}