{"gene":"CPT1B","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2002,"finding":"CPT1B (muscle-type carnitine palmitoyltransferase I) encodes a key enzyme controlling beta-oxidation of long-chain fatty acids in heart and skeletal muscle; the gene has two promoters in humans, mice, sheep, and rats, and splice variants in the coding region do not produce CPT1 enzymatic activity when expressed in Pichia pastoris, arguing against splice variation as a mechanism of malonyl-CoA sensitivity modulation.","method":"cDNA/genomic sequencing, expression in Pichia pastoris (in vitro enzymatic activity assay), fluorescent in situ hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in yeast expression system with activity assay, combined with structural/genomic characterization","pmids":["12015320"],"is_preprint":false},{"year":1997,"finding":"The human CPT1B gene maps to chromosome 22qter (distinct from the liver-type CPT1A locus), contains an untranslated 5' exon, and undergoes alternative splicing of introns 13 and 19, with intron 13 splicing causing an in-frame deletion producing a protein 10 amino acids smaller.","method":"cDNA and genomic DNA sequencing, fluorescent in situ hybridization (FISH)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 — direct chromosomal mapping plus structural characterization of splice variants by sequencing","pmids":["9199240"],"is_preprint":false},{"year":1998,"finding":"Mouse Cpt1b maps to chromosome 15 (distinct from Cpt1a on chromosome 19), confirming that the liver-type and muscle-type CPT1 isoforms are encoded by different loci at separate chromosomal positions.","method":"Chromosomal mapping using mouse mapping panel, cDNA probes","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"High","confidence_rationale":"Tier 2 — direct chromosomal mapping with no pseudogenes detected","pmids":["9680378"],"is_preprint":false},{"year":2018,"finding":"Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating the rate of cardiac fatty acid oxidation; a knock-in mouse expressing CPT1B-E3A (reduced malonyl-CoA sensitivity) showed 1.9-fold higher FAO in isolated perfused hearts, with compensatory downregulation of CPT1B protein and FAO gene expression.","method":"Knock-in mouse model (CPT1B-E3A mutant), isolated perfused heart FAO assay, metabolomics, proteomics, transcriptomics","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 — in vivo mutagenesis knock-in + multiple orthogonal assays (metabolomics, proteomics, transcriptomics, functional perfusion)","pmids":["29635338"],"is_preprint":false},{"year":2021,"finding":"PHD2/3 (prolyl hydroxylases) bind to CPT1B and promote hydroxylation of CPT1B at proline-295 (P295); this hydroxylation is required for CPT1B interaction with VDAC1 and for long-chain fatty acid beta-oxidation in cardiomyocytes. A CPT1B-P295A mutant constitutively binds VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes.","method":"Co-immunoprecipitation, site-directed mutagenesis (CPT1B-P295A), PHD2/3 knockout mice, high-fat diet model, rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis identifying specific PTM site, Co-IP identifying binding partners, in vivo genetic model with rescue","pmids":["34610308"],"is_preprint":false},{"year":2025,"finding":"TEX44 interacts with CPT1B in sperm mitochondria to form a 'mitochondrial glue' anchoring adjacent mitochondria for assembly of the sperm-specific mitochondrial sheath; purified TEX44 protein modulates CPT1B enzymatic activity, limiting conversion of long-chain fatty acids (palmitic and myristic acid) into acylcarnitines and thereby reducing ROS. Loss of TEX44 leads to unregulated FAO, excessive ROS, and sperm DNA/flagellar damage. Germ-cell-specific Cpt1b knockout mice exhibit mitochondrial sheath defects and reduced sperm motility similar to TEX44 deficiency.","method":"Whole-exome sequencing, Tex44 knockout mice, germ-cell-specific Cpt1b knockout mice, in vitro purified TEX44 protein enzymatic modulation assay, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay with purified protein, reciprocal genetic KO models, Co-IP, human patient variants","pmids":["40849303"],"is_preprint":false},{"year":2015,"finding":"CPT1B promoter activity in skeletal muscle is regulated by epigenetic modifications: in severely obese women, blunted CPT1B expression in response to lipid is accompanied by CpG hypermethylation, reduced H3/H4 histone acetylation, and altered occupancy of PPARδ and HNF4α; methylation of specific CpG sites blocks binding of the transcription factor USF at the CPT1B promoter.","method":"Primary human skeletal muscle cultures, real-time PCR, chromatin immunoprecipitation (ChIP), bisulfite sequencing (CpG methylation), histone acetylation assays, transcription factor binding assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal epigenetic and transcriptional methods in human primary cells","pmids":["26058865"],"is_preprint":false},{"year":2014,"finding":"MEF2A binds to a specific MEF2 site in the Cpt1b promoter and activates Cpt1b transcription; exercise training increases MEF2A binding and MEF2A acetylation at the Cpt1b promoter while decreasing HDAC5 and HDAC3 binding to MEF2A and to the promoter. HDAC5 phosphorylation (Ser259/Ser498) by exercise causes its nuclear export, derepressing MEF2A-dependent Cpt1b transcription.","method":"Chromatin immunoprecipitation (ChIP), MEF2A overexpression in C2C12 myoblasts, luciferase promoter assay, mouse treadmill exercise model, Western blot","journal":"Acta physiologica (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 — ChIP in vivo and in vitro, luciferase assay, gain-of-function, multiple orthogonal methods","pmids":["25213552"],"is_preprint":false},{"year":2019,"finding":"EZH2 binds to the CPT1B promoter via H3K27me3 (trimethylation of lysine 27 of histone H3) to suppress CPT1B transcription during cardiac hypertrophy; the long noncoding RNA uc.323 interacts with EZH2 and its downregulation (via mTORC1) leads to reduced CPT1B expression and cardiomyocyte hypertrophy. CPT1B overexpression blocks uc.323-mediated cardiomyocyte hypertrophy.","method":"Chromatin immunoprecipitation (ChIP), lncRNA microarray, mRNA microarray, gain/loss-of-function experiments in cardiomyocytes, aortic banding mouse model","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating EZH2/H3K27me3 occupancy at CPT1B promoter, genetic rescue experiments, in vivo model","pmids":["31735087"],"is_preprint":false},{"year":2020,"finding":"miR-138-5p directly targets the CPT1B 3'UTR to suppress its expression; miR-138-5p inhibitor increases CPT1B expression while mimic reduces it, and mutation of CPT1B abrogates this regulation. CPT1B upregulation by GJLZ decoction in NAFLD is mediated through suppression of miR-138-5p.","method":"Dual-luciferase reporter assay, miRNA mimic/inhibitor, RT-PCR, Western blot, rat NAFLD model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase with mutation confirms direct miRNA-mRNA interaction, supported by in vivo model","pmids":["32325349"],"is_preprint":false},{"year":2020,"finding":"Androgen receptor (AR) inhibits CPT1B transcription via specific AR-binding sites in the CPT1B promoter, confirmed by dual-luciferase assay and ChIP; in CRPC cells, CPT1B overexpression increases AKT expression and phosphorylation.","method":"Dual-luciferase assay, ChIP assay, stable knockdown/overexpression cell lines, Western blot","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm AR binding at CPT1B promoter, downstream AKT signaling by Western blot","pmids":["32648618"],"is_preprint":false},{"year":2022,"finding":"SMAD3, a transcription factor downstream of myostatin (Mstn), directly binds to the Cpt1b promoter to regulate its transcription; Mstn knockdown upregulates Cpt1b expression and CPT1 enzyme activity in skeletal muscle, promoting beta-oxidation.","method":"Chromatin immunoprecipitation (ChIP), CPT1 enzyme activity assay, RT-PCR, RNA interference mouse model","journal":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct SMAD3 binding at Cpt1b promoter, supported by enzyme activity assay","pmids":["36002433"],"is_preprint":false},{"year":2019,"finding":"In LRP6-deficient hearts, Drp1 activation leads to decreased CPT1B expression and lipid accumulation; Drp1 inhibitor restores CPT1B levels and reduces fatty acid accumulation. c-Myc (but not CTCF) is identified as a transcriptional regulator of CPT1B in cardiomyocytes.","method":"Cardiac-specific LRP6 knockout mice, GC-FID/MS fatty acid analysis, Drp1 inhibitor treatment, in vitro c-Myc overexpression/knockdown","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic model with downstream pathway, in vitro TF identification; c-Myc regulation of CPT1B not confirmed by ChIP","pmids":["31811407"],"is_preprint":false},{"year":2016,"finding":"Cardiac-specific knockdown of CPT1B via lentiviral injection in obese mice protected against HFD-induced cardiac remodeling, decreasing heart weight/tibial length ratio, improving ejection fraction, reducing reactive oxygen species and lipid accumulation in cardiomyocytes, and partially preserving myocardial ultrastructure.","method":"Intramyocardial lentivirus injection for CPT1B knockdown, echocardiography, histology, ROS assay, electron microscopy, biochemical assays in mouse obesity model","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — clean tissue-specific KD with multiple functional readouts in vivo","pmids":["27804274"],"is_preprint":false},{"year":2025,"finding":"AAV-mediated cardiac overexpression of CPT1B in neonatal rat cardiomyocytes attenuated phenylephrine-induced hypertrophy and decreased mitochondrial ROS; in mice subjected to transverse aortic constriction, cardiac CPT1B overexpression attenuated cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction.","method":"AAV gene transfer, neonatal rat cardiomyocyte culture, transverse aortic constriction mouse model, echocardiography, histology, ROS measurement","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function AAV in vitro and in vivo with multiple functional readouts","pmids":["40646338"],"is_preprint":false},{"year":2024,"finding":"CPT1B interacts with KEAP1 (Kelch-like ECH-associated protein 1); CPT1B knockdown leads to decreased NRF2 expression and induction of ferroptosis in pancreatic cancer cells, linking CPT1B to the KEAP1/NRF2 redox homeostasis axis.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, flow cytometry, confocal fluorescence microscopy, transmission electron microscopy, animal xenograft model","journal":"Surgery","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP identifying KEAP1 as binding partner, supported by functional KD experiments","pmids":["38302326"],"is_preprint":false},{"year":2024,"finding":"ZNF263 binds to the CPT1B promoter to activate its transcription, enhancing fatty acid beta-oxidation and promoting cisplatin resistance in lung adenocarcinoma cells; CPT1B-mediated resistance is abrogated by FAO inhibitor etomoxir.","method":"Dual-luciferase assay, chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, CCK-8, FAO rate assay","journal":"The pharmacogenomics journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct TF-promoter interaction, functional rescue with FAO inhibitor","pmids":["39500874"],"is_preprint":false},{"year":2023,"finding":"MITF (microphthalmia-associated transcription factor) binds the CPT1B promoter and inhibits CPT1B transcription, reducing fatty acid beta-oxidation and suppressing cancer stem cell stemness in lung adenocarcinoma cells.","method":"Dual-luciferase assay, ChIP assay, qRT-PCR, FAO assay, sphere-forming assay","journal":"Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct MITF binding at CPT1B promoter with functional FAO readout","pmids":["38016436"],"is_preprint":false},{"year":2021,"finding":"ANXA1 (Annexin A1) regulates CPT1B expression via the FPR2/ALX-AMPK-PPARα signaling axis in proximal tubular epithelial cells; ANXA1 silencing suppresses phosphorylated AMPK (Thr172), leading to decreased PPARα and CPT1B expression and increased lipid accumulation.","method":"siRNA knockdown, Western blot, lipid accumulation assay, phospho-AMPK assay, high-glucose/palmitate treatment of human PTECs","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway ordering by genetic KD with multiple molecular readouts; mechanism is correlative at CPT1B level","pmids":["34103347"],"is_preprint":false},{"year":2021,"finding":"In aged skeletal muscle, CPT1B protein specifically declines under high-fat diet conditions while other beta-oxidation proteins are upregulated, and computational flux modeling identifies CPT1B as the primary controller of FAO flux, causing loss of metabolic flexibility and contributing to insulin resistance.","method":"Proteomics, lipidomics, mitochondrial function analysis, computational metabolic flux modeling in young vs. aged mice on low-fat or high-fat diet","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with computational modeling identifies CPT1B as rate-controlling enzyme in aged muscle","pmids":["34330275"],"is_preprint":false},{"year":2024,"finding":"STAT3 directly binds to the CPT1B promoter/gene region in pancreatic cancer stem cells, regulating CPT1B expression and thereby affecting lipid/energy metabolism; quercetin inhibits CPT1B via STAT3 suppression.","method":"Chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, siRNA/overexpression of STAT3","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single ChIP experiment with limited mechanistic follow-up","pmids":["40412371"],"is_preprint":false},{"year":2013,"finding":"CB1 (cannabinoid receptor 1) regulates CPT1B mRNA expression in porcine intramuscular adipocytes; CB1 agonist Δ9-THC decreases CPT1B expression and increases lipid accumulation, while the CB1 antagonist SR141716 increases CPT1B expression and reduces lipid accumulation. CB1 is upstream of CPT1B; CPT1 antagonist etomoxir does not affect CB1 expression.","method":"Pharmacological treatment (Δ9-THC and SR141716), RT-PCR, lipid accumulation assay in porcine intramuscular adipocytes","journal":"Animal genetics","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological manipulation without direct binding/promoter evidence; pathway ordering by negative result with etomoxir","pmids":["23914904"],"is_preprint":false},{"year":2024,"finding":"cpt1b regulates cardiomyocyte proliferation in zebrafish; cpt1b knockout impairs proliferation while cardiomyocyte-specific overexpression promotes it. RNA-seq and pharmacological studies identified glutamine synthetase as a key downstream effector of cpt1b in cardiomyocyte proliferation.","method":"cpt1b knockout zebrafish, cardiomyocyte-specific overexpression, RNA-seq, pharmacological inhibition","journal":"Journal of cardiovascular development and disease","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO and overexpression with transcriptomic and pharmacological identification of downstream effector in zebrafish ortholog","pmids":["39590187"],"is_preprint":false},{"year":2023,"finding":"ABHD5 regulates placental lipid droplet storage through CPT1B; knockdown of ABHD5 increases lipid droplet accumulation in syncytiotrophoblast cells, and this effect is attenuated by downregulation of CPT1B, placing CPT1B downstream of ABHD5 in placental lipid metabolism.","method":"siRNA knockdown in BeWo cell syncytiotrophoblast model, lipid droplet staining, high-glucose stimulation, scRNA-seq validation","journal":"Archives of medical research","confidence":"Low","confidence_rationale":"Tier 3 — genetic epistasis by double KD; mechanistic link between ABHD5 and CPT1B not directly defined","pmids":["38042031"],"is_preprint":false}],"current_model":"CPT1B (muscle-type carnitine palmitoyltransferase I) is the rate-limiting enzyme for mitochondrial long-chain fatty acid beta-oxidation in heart and skeletal muscle, catalyzing transfer of acyl groups from acyl-CoA to carnitine; its activity is inhibited by malonyl-CoA (via a critical E3A site), and is regulated by post-translational hydroxylation at P295 by PHD2/3 (required for interaction with VDAC1 and FAO), by transcriptional control through MEF2A/HDAC5, EZH2/H3K27me3, AR, MITF, SMAD3, ZNF263, and STAT3, by miRNA-mediated suppression (miR-138-5p), and by physical interaction with TEX44 in sperm mitochondria that modulates CPT1B enzymatic activity and limits ROS production."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that human CPT1B is a distinct gene at 22qter with its own alternative splicing pattern resolved the question of how muscle-type and liver-type CPT1 isoforms are independently encoded.","evidence":"cDNA/genomic sequencing and FISH mapping of human CPT1B","pmids":["9199240"],"confidence":"High","gaps":["Functional consequences of the intron 13 splice variant (10 aa deletion) not tested enzymatically","Regulatory differences between two CPT1B promoters not addressed"]},{"year":2002,"claim":"Demonstrating that CPT1B splice variants lack enzymatic activity when expressed in Pichia pastoris ruled out alternative splicing as a mechanism for modulating malonyl-CoA sensitivity, reinforcing that allosteric regulation is the primary control point.","evidence":"Heterologous expression in Pichia pastoris with enzymatic activity assay","pmids":["12015320"],"confidence":"High","gaps":["The structural determinants of malonyl-CoA sensitivity not mapped at the residue level","Whether splice variants have non-enzymatic functions not tested"]},{"year":2014,"claim":"Identifying MEF2A as a direct transcriptional activator of Cpt1b whose activity is derepressed by exercise-induced HDAC5 phosphorylation and nuclear export established the first defined transcription factor–promoter mechanism for exercise-induced FAO gene upregulation in skeletal muscle.","evidence":"ChIP, luciferase promoter assay, MEF2A overexpression in C2C12 myoblasts, mouse treadmill exercise model","pmids":["25213552"],"confidence":"High","gaps":["Whether MEF2A is sufficient for exercise-induced CPT1B upregulation or acts in combination with other factors","HDAC3 contribution at the CPT1B promoter not dissected independently of HDAC5"]},{"year":2015,"claim":"Showing that CpG hypermethylation at the CPT1B promoter blocks USF binding and blunts lipid-responsive CPT1B induction in obese human muscle revealed an epigenetic layer of CPT1B regulation with metabolic disease relevance.","evidence":"Bisulfite sequencing, ChIP, histone acetylation assays in primary human skeletal muscle cultures from obese vs. lean women","pmids":["26058865"],"confidence":"High","gaps":["Whether methylation changes are cause or consequence of obesity not determined","Writers/erasers responsible for CPT1B promoter methylation not identified"]},{"year":2018,"claim":"The CPT1B-E3A knock-in mouse provided direct in vivo evidence that malonyl-CoA inhibition is the rate-limiting control point for cardiac FAO, as relieving this inhibition increased FAO ~1.9-fold with compensatory transcriptional feedback.","evidence":"CPT1B-E3A knock-in mice, isolated perfused heart FAO assay, multi-omics","pmids":["29635338"],"confidence":"High","gaps":["Whether chronic loss of malonyl-CoA sensitivity causes cardiac pathology under stress conditions","The identity of the feedback sensor linking FAO flux to CPT1B transcription is unknown"]},{"year":2019,"claim":"EZH2-mediated H3K27me3 at the CPT1B promoter was shown to suppress CPT1B transcription during cardiac hypertrophy, establishing a Polycomb-group epigenetic silencing mechanism controlled upstream by mTORC1 and the lncRNA uc.323.","evidence":"ChIP for EZH2/H3K27me3, lncRNA microarray, gain/loss-of-function in cardiomyocytes, aortic banding mouse model","pmids":["31735087"],"confidence":"High","gaps":["Whether EZH2 recruitment is specific to CPT1B or part of a broader FAO gene silencing program","Direct interaction between uc.323 and EZH2 at the CPT1B locus not confirmed by CLIP or similar"]},{"year":2020,"claim":"Multiple transcription factors were shown to directly bind the CPT1B promoter—AR as a repressor and miR-138-5p as a post-transcriptional silencer—expanding the regulatory network controlling CPT1B expression in contexts ranging from prostate cancer to NAFLD.","evidence":"ChIP and dual-luciferase for AR (prostate cancer cells); dual-luciferase with 3′UTR mutation for miR-138-5p (rat NAFLD model)","pmids":["32648618","32325349"],"confidence":"Medium","gaps":["AR-CPT1B axis not validated in non-cancer tissues","Physiological relevance of miR-138-5p regulation of CPT1B outside of the NAFLD model unclear"]},{"year":2021,"claim":"Discovery that PHD2/3-mediated prolyl hydroxylation at P295 is required for CPT1B–VDAC1 interaction and functional FAO revealed a novel oxygen-sensing post-translational control of mitochondrial fatty acid import.","evidence":"Co-IP, CPT1B-P295A mutagenesis, PHD2/3 KO mice, high-fat diet rescue experiments in cardiomyocytes","pmids":["34610308"],"confidence":"High","gaps":["Structural basis of how P295 hydroxylation promotes VDAC1 binding not resolved","Whether other mitochondrial outer membrane partners are regulated by this hydroxylation is unknown"]},{"year":2021,"claim":"Multi-omic analysis of aged skeletal muscle identified CPT1B as the specific protein whose decline under high-fat diet causes loss of metabolic flexibility, positioning it as the dominant flux controller of FAO in aging.","evidence":"Proteomics, lipidomics, mitochondrial function analysis, computational metabolic flux modeling in young vs. aged mice","pmids":["34330275"],"confidence":"Medium","gaps":["Whether restoring CPT1B levels rescues metabolic flexibility in aged muscle not tested","Mechanism of age-specific CPT1B protein decline not defined"]},{"year":2022,"claim":"SMAD3 was identified as a direct CPT1B promoter-binding transcription factor downstream of myostatin signaling, linking the myostatin–SMAD3 axis to FAO regulation in skeletal muscle.","evidence":"ChIP, CPT1 enzyme activity assay, Mstn knockdown in mouse skeletal muscle","pmids":["36002433"],"confidence":"Medium","gaps":["Whether SMAD3 acts as activator or repressor at the Cpt1b promoter not fully resolved","Contribution relative to other SMAD isoforms not addressed"]},{"year":2023,"claim":"MITF was identified as a transcriptional repressor of CPT1B in lung adenocarcinoma, directly linking FAO suppression to cancer stem cell stemness regulation.","evidence":"ChIP and dual-luciferase assay confirming MITF binding at CPT1B promoter, FAO and sphere-forming assays","pmids":["38016436"],"confidence":"Medium","gaps":["Whether MITF regulation of CPT1B occurs in non-cancer melanocytic or muscle lineages","Downstream metabolic intermediates linking reduced FAO to stemness not identified"]},{"year":2024,"claim":"CPT1B was found to interact with KEAP1, and its knockdown reduces NRF2 and induces ferroptosis in pancreatic cancer cells, suggesting a non-canonical role in redox homeostasis beyond its enzymatic function.","evidence":"Co-immunoprecipitation, siRNA knockdown, ferroptosis markers, xenograft model","pmids":["38302326"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation or domain mapping","Whether KEAP1 interaction depends on CPT1B enzymatic activity or is a scaffolding role not determined","Relevance outside pancreatic cancer not tested"]},{"year":2024,"claim":"ZNF263 was identified as a transcriptional activator of CPT1B promoting cisplatin resistance through enhanced FAO in lung adenocarcinoma, demonstrating that CPT1B-driven FAO can be co-opted for drug resistance.","evidence":"ChIP and dual-luciferase at CPT1B promoter, FAO rate assay, etomoxir rescue","pmids":["39500874"],"confidence":"Medium","gaps":["Whether ZNF263 regulates CPT1B in normal muscle or heart tissue","Specificity of ZNF263 for CPT1B versus other FAO genes not assessed"]},{"year":2025,"claim":"TEX44 was discovered to physically interact with CPT1B in sperm mitochondria, directly modulating its enzymatic activity to limit excess ROS from unregulated FAO; germ-cell-specific Cpt1b KO phenocopied TEX44 deficiency, establishing CPT1B as essential for mitochondrial sheath assembly and male fertility.","evidence":"Tex44 KO and germ-cell-specific Cpt1b KO mice, purified TEX44 protein modulating CPT1B activity in vitro, Co-IP, human patient exome sequencing","pmids":["40849303"],"confidence":"High","gaps":["Structural basis of TEX44–CPT1B interaction not defined","Whether TEX44 modulation involves allosteric inhibition or substrate competition unknown"]},{"year":2025,"claim":"AAV-mediated cardiac CPT1B overexpression attenuated pressure-overload-induced hypertrophy and fibrosis, providing direct gain-of-function evidence that maintaining CPT1B levels is cardioprotective.","evidence":"AAV gene transfer in neonatal rat cardiomyocytes and transverse aortic constriction mouse model with echocardiography and histology","pmids":["40646338"],"confidence":"Medium","gaps":["Whether cardioprotection is solely via increased FAO or involves non-enzymatic CPT1B functions","Long-term effects of sustained CPT1B overexpression not evaluated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of malonyl-CoA inhibition and PHD-mediated hydroxylation effects on CPT1B conformation, how the extensive transcriptional regulatory network is integrated in a tissue- and context-specific manner, and whether non-enzymatic roles (e.g., KEAP1 interaction, scaffolding in sperm mitochondria) represent a general moonlighting function of CPT1B.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length CPT1B with malonyl-CoA or VDAC1","Tissue-specific integration of multiple TF inputs not modeled","Non-enzymatic roles lack structural or reconstitution-level evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,4,5,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,10,16,17]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5]}],"complexes":[],"partners":["VDAC1","TEX44","KEAP1","EZH2","MEF2A","HDAC5","SMAD3"],"other_free_text":[]},"mechanistic_narrative":"CPT1B is the muscle-type carnitine palmitoyltransferase I that catalyzes the rate-limiting step of mitochondrial long-chain fatty acid β-oxidation in heart and skeletal muscle by transferring acyl groups from acyl-CoA to carnitine [PMID:12015320, PMID:34330275]. Its enzymatic activity is allosterically inhibited by malonyl-CoA, and a knock-in mouse expressing a malonyl-CoA–insensitive mutant (E3A) shows nearly twofold elevated cardiac fatty acid oxidation with compensatory transcriptional downregulation of FAO genes [PMID:29635338]. Post-translationally, prolyl hydroxylation at P295 by PHD2/3 is required for CPT1B interaction with VDAC1 and for functional long-chain fatty acid oxidation in cardiomyocytes [PMID:34610308]. CPT1B transcription is regulated by a network of activators and repressors—including MEF2A/HDAC5, EZH2-mediated H3K27me3, AR, MITF, ZNF263, and SMAD3—and in sperm mitochondria, TEX44 physically modulates CPT1B activity to limit ROS production, with germ-cell-specific Cpt1b knockout causing mitochondrial sheath defects and impaired sperm motility [PMID:25213552, PMID:31735087, PMID:40849303]."},"prefetch_data":{"uniprot":{"accession":"Q92523","full_name":"Carnitine O-palmitoyltransferase 1, muscle isoform","aliases":["Carnitine O-palmitoyltransferase I, muscle isoform","CPT I","CPTI-M","Carnitine palmitoyltransferase 1B","Carnitine palmitoyltransferase I-like protein"],"length_aa":772,"mass_kda":87.8,"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","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q92523/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPT1B","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPT1B","total_profiled":1310},"omim":[{"mim_id":"612417","title":"NARCOLEPSY 4, SUSCEPTIBILITY TO; 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against splice variation as a mechanism of malonyl-CoA sensitivity modulation.\",\n      \"method\": \"cDNA/genomic sequencing, expression in Pichia pastoris (in vitro enzymatic activity assay), fluorescent in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in yeast expression system with activity assay, combined with structural/genomic characterization\",\n      \"pmids\": [\"12015320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human CPT1B gene maps to chromosome 22qter (distinct from the liver-type CPT1A locus), contains an untranslated 5' exon, and undergoes alternative splicing of introns 13 and 19, with intron 13 splicing causing an in-frame deletion producing a protein 10 amino acids smaller.\",\n      \"method\": \"cDNA and genomic DNA sequencing, fluorescent in situ hybridization (FISH)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct chromosomal mapping plus structural characterization of splice variants by sequencing\",\n      \"pmids\": [\"9199240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse Cpt1b maps to chromosome 15 (distinct from Cpt1a on chromosome 19), confirming that the liver-type and muscle-type CPT1 isoforms are encoded by different loci at separate chromosomal positions.\",\n      \"method\": \"Chromosomal mapping using mouse mapping panel, cDNA probes\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping with no pseudogenes detected\",\n      \"pmids\": [\"9680378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating the rate of cardiac fatty acid oxidation; a knock-in mouse expressing CPT1B-E3A (reduced malonyl-CoA sensitivity) showed 1.9-fold higher FAO in isolated perfused hearts, with compensatory downregulation of CPT1B protein and FAO gene expression.\",\n      \"method\": \"Knock-in mouse model (CPT1B-E3A mutant), isolated perfused heart FAO assay, metabolomics, proteomics, transcriptomics\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo mutagenesis knock-in + multiple orthogonal assays (metabolomics, proteomics, transcriptomics, functional perfusion)\",\n      \"pmids\": [\"29635338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHD2/3 (prolyl hydroxylases) bind to CPT1B and promote hydroxylation of CPT1B at proline-295 (P295); this hydroxylation is required for CPT1B interaction with VDAC1 and for long-chain fatty acid beta-oxidation in cardiomyocytes. A CPT1B-P295A mutant constitutively binds VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (CPT1B-P295A), PHD2/3 knockout mice, high-fat diet model, rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying specific PTM site, Co-IP identifying binding partners, in vivo genetic model with rescue\",\n      \"pmids\": [\"34610308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEX44 interacts with CPT1B in sperm mitochondria to form a 'mitochondrial glue' anchoring adjacent mitochondria for assembly of the sperm-specific mitochondrial sheath; purified TEX44 protein modulates CPT1B enzymatic activity, limiting conversion of long-chain fatty acids (palmitic and myristic acid) into acylcarnitines and thereby reducing ROS. Loss of TEX44 leads to unregulated FAO, excessive ROS, and sperm DNA/flagellar damage. Germ-cell-specific Cpt1b knockout mice exhibit mitochondrial sheath defects and reduced sperm motility similar to TEX44 deficiency.\",\n      \"method\": \"Whole-exome sequencing, Tex44 knockout mice, germ-cell-specific Cpt1b knockout mice, in vitro purified TEX44 protein enzymatic modulation assay, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay with purified protein, reciprocal genetic KO models, Co-IP, human patient variants\",\n      \"pmids\": [\"40849303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPT1B promoter activity in skeletal muscle is regulated by epigenetic modifications: in severely obese women, blunted CPT1B expression in response to lipid is accompanied by CpG hypermethylation, reduced H3/H4 histone acetylation, and altered occupancy of PPARδ and HNF4α; methylation of specific CpG sites blocks binding of the transcription factor USF at the CPT1B promoter.\",\n      \"method\": \"Primary human skeletal muscle cultures, real-time PCR, chromatin immunoprecipitation (ChIP), bisulfite sequencing (CpG methylation), histone acetylation assays, transcription factor binding assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal epigenetic and transcriptional methods in human primary cells\",\n      \"pmids\": [\"26058865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MEF2A binds to a specific MEF2 site in the Cpt1b promoter and activates Cpt1b transcription; exercise training increases MEF2A binding and MEF2A acetylation at the Cpt1b promoter while decreasing HDAC5 and HDAC3 binding to MEF2A and to the promoter. HDAC5 phosphorylation (Ser259/Ser498) by exercise causes its nuclear export, derepressing MEF2A-dependent Cpt1b transcription.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), MEF2A overexpression in C2C12 myoblasts, luciferase promoter assay, mouse treadmill exercise model, Western blot\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP in vivo and in vitro, luciferase assay, gain-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"25213552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EZH2 binds to the CPT1B promoter via H3K27me3 (trimethylation of lysine 27 of histone H3) to suppress CPT1B transcription during cardiac hypertrophy; the long noncoding RNA uc.323 interacts with EZH2 and its downregulation (via mTORC1) leads to reduced CPT1B expression and cardiomyocyte hypertrophy. CPT1B overexpression blocks uc.323-mediated cardiomyocyte hypertrophy.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), lncRNA microarray, mRNA microarray, gain/loss-of-function experiments in cardiomyocytes, aortic banding mouse model\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating EZH2/H3K27me3 occupancy at CPT1B promoter, genetic rescue experiments, in vivo model\",\n      \"pmids\": [\"31735087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-138-5p directly targets the CPT1B 3'UTR to suppress its expression; miR-138-5p inhibitor increases CPT1B expression while mimic reduces it, and mutation of CPT1B abrogates this regulation. CPT1B upregulation by GJLZ decoction in NAFLD is mediated through suppression of miR-138-5p.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor, RT-PCR, Western blot, rat NAFLD model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase with mutation confirms direct miRNA-mRNA interaction, supported by in vivo model\",\n      \"pmids\": [\"32325349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Androgen receptor (AR) inhibits CPT1B transcription via specific AR-binding sites in the CPT1B promoter, confirmed by dual-luciferase assay and ChIP; in CRPC cells, CPT1B overexpression increases AKT expression and phosphorylation.\",\n      \"method\": \"Dual-luciferase assay, ChIP assay, stable knockdown/overexpression cell lines, Western blot\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm AR binding at CPT1B promoter, downstream AKT signaling by Western blot\",\n      \"pmids\": [\"32648618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMAD3, a transcription factor downstream of myostatin (Mstn), directly binds to the Cpt1b promoter to regulate its transcription; Mstn knockdown upregulates Cpt1b expression and CPT1 enzyme activity in skeletal muscle, promoting beta-oxidation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), CPT1 enzyme activity assay, RT-PCR, RNA interference mouse model\",\n      \"journal\": \"Sheng wu gong cheng xue bao = Chinese journal of biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct SMAD3 binding at Cpt1b promoter, supported by enzyme activity assay\",\n      \"pmids\": [\"36002433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In LRP6-deficient hearts, Drp1 activation leads to decreased CPT1B expression and lipid accumulation; Drp1 inhibitor restores CPT1B levels and reduces fatty acid accumulation. c-Myc (but not CTCF) is identified as a transcriptional regulator of CPT1B in cardiomyocytes.\",\n      \"method\": \"Cardiac-specific LRP6 knockout mice, GC-FID/MS fatty acid analysis, Drp1 inhibitor treatment, in vitro c-Myc overexpression/knockdown\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic model with downstream pathway, in vitro TF identification; c-Myc regulation of CPT1B not confirmed by ChIP\",\n      \"pmids\": [\"31811407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cardiac-specific knockdown of CPT1B via lentiviral injection in obese mice protected against HFD-induced cardiac remodeling, decreasing heart weight/tibial length ratio, improving ejection fraction, reducing reactive oxygen species and lipid accumulation in cardiomyocytes, and partially preserving myocardial ultrastructure.\",\n      \"method\": \"Intramyocardial lentivirus injection for CPT1B knockdown, echocardiography, histology, ROS assay, electron microscopy, biochemical assays in mouse obesity model\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KD with multiple functional readouts in vivo\",\n      \"pmids\": [\"27804274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AAV-mediated cardiac overexpression of CPT1B in neonatal rat cardiomyocytes attenuated phenylephrine-induced hypertrophy and decreased mitochondrial ROS; in mice subjected to transverse aortic constriction, cardiac CPT1B overexpression attenuated cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction.\",\n      \"method\": \"AAV gene transfer, neonatal rat cardiomyocyte culture, transverse aortic constriction mouse model, echocardiography, histology, ROS measurement\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function AAV in vitro and in vivo with multiple functional readouts\",\n      \"pmids\": [\"40646338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1B interacts with KEAP1 (Kelch-like ECH-associated protein 1); CPT1B knockdown leads to decreased NRF2 expression and induction of ferroptosis in pancreatic cancer cells, linking CPT1B to the KEAP1/NRF2 redox homeostasis axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, flow cytometry, confocal fluorescence microscopy, transmission electron microscopy, animal xenograft model\",\n      \"journal\": \"Surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying KEAP1 as binding partner, supported by functional KD experiments\",\n      \"pmids\": [\"38302326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF263 binds to the CPT1B promoter to activate its transcription, enhancing fatty acid beta-oxidation and promoting cisplatin resistance in lung adenocarcinoma cells; CPT1B-mediated resistance is abrogated by FAO inhibitor etomoxir.\",\n      \"method\": \"Dual-luciferase assay, chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, CCK-8, FAO rate assay\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct TF-promoter interaction, functional rescue with FAO inhibitor\",\n      \"pmids\": [\"39500874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MITF (microphthalmia-associated transcription factor) binds the CPT1B promoter and inhibits CPT1B transcription, reducing fatty acid beta-oxidation and suppressing cancer stem cell stemness in lung adenocarcinoma cells.\",\n      \"method\": \"Dual-luciferase assay, ChIP assay, qRT-PCR, FAO assay, sphere-forming assay\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct MITF binding at CPT1B promoter with functional FAO readout\",\n      \"pmids\": [\"38016436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 (Annexin A1) regulates CPT1B expression via the FPR2/ALX-AMPK-PPARα signaling axis in proximal tubular epithelial cells; ANXA1 silencing suppresses phosphorylated AMPK (Thr172), leading to decreased PPARα and CPT1B expression and increased lipid accumulation.\",\n      \"method\": \"siRNA knockdown, Western blot, lipid accumulation assay, phospho-AMPK assay, high-glucose/palmitate treatment of human PTECs\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway ordering by genetic KD with multiple molecular readouts; mechanism is correlative at CPT1B level\",\n      \"pmids\": [\"34103347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In aged skeletal muscle, CPT1B protein specifically declines under high-fat diet conditions while other beta-oxidation proteins are upregulated, and computational flux modeling identifies CPT1B as the primary controller of FAO flux, causing loss of metabolic flexibility and contributing to insulin resistance.\",\n      \"method\": \"Proteomics, lipidomics, mitochondrial function analysis, computational metabolic flux modeling in young vs. aged mice on low-fat or high-fat diet\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with computational modeling identifies CPT1B as rate-controlling enzyme in aged muscle\",\n      \"pmids\": [\"34330275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAT3 directly binds to the CPT1B promoter/gene region in pancreatic cancer stem cells, regulating CPT1B expression and thereby affecting lipid/energy metabolism; quercetin inhibits CPT1B via STAT3 suppression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, siRNA/overexpression of STAT3\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single ChIP experiment with limited mechanistic follow-up\",\n      \"pmids\": [\"40412371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CB1 (cannabinoid receptor 1) regulates CPT1B mRNA expression in porcine intramuscular adipocytes; CB1 agonist Δ9-THC decreases CPT1B expression and increases lipid accumulation, while the CB1 antagonist SR141716 increases CPT1B expression and reduces lipid accumulation. CB1 is upstream of CPT1B; CPT1 antagonist etomoxir does not affect CB1 expression.\",\n      \"method\": \"Pharmacological treatment (Δ9-THC and SR141716), RT-PCR, lipid accumulation assay in porcine intramuscular adipocytes\",\n      \"journal\": \"Animal genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological manipulation without direct binding/promoter evidence; pathway ordering by negative result with etomoxir\",\n      \"pmids\": [\"23914904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"cpt1b regulates cardiomyocyte proliferation in zebrafish; cpt1b knockout impairs proliferation while cardiomyocyte-specific overexpression promotes it. RNA-seq and pharmacological studies identified glutamine synthetase as a key downstream effector of cpt1b in cardiomyocyte proliferation.\",\n      \"method\": \"cpt1b knockout zebrafish, cardiomyocyte-specific overexpression, RNA-seq, pharmacological inhibition\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO and overexpression with transcriptomic and pharmacological identification of downstream effector in zebrafish ortholog\",\n      \"pmids\": [\"39590187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ABHD5 regulates placental lipid droplet storage through CPT1B; knockdown of ABHD5 increases lipid droplet accumulation in syncytiotrophoblast cells, and this effect is attenuated by downregulation of CPT1B, placing CPT1B downstream of ABHD5 in placental lipid metabolism.\",\n      \"method\": \"siRNA knockdown in BeWo cell syncytiotrophoblast model, lipid droplet staining, high-glucose stimulation, scRNA-seq validation\",\n      \"journal\": \"Archives of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis by double KD; mechanistic link between ABHD5 and CPT1B not directly defined\",\n      \"pmids\": [\"38042031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPT1B (muscle-type carnitine palmitoyltransferase I) is the rate-limiting enzyme for mitochondrial long-chain fatty acid beta-oxidation in heart and skeletal muscle, catalyzing transfer of acyl groups from acyl-CoA to carnitine; its activity is inhibited by malonyl-CoA (via a critical E3A site), and is regulated by post-translational hydroxylation at P295 by PHD2/3 (required for interaction with VDAC1 and FAO), by transcriptional control through MEF2A/HDAC5, EZH2/H3K27me3, AR, MITF, SMAD3, ZNF263, and STAT3, by miRNA-mediated suppression (miR-138-5p), and by physical interaction with TEX44 in sperm mitochondria that modulates CPT1B enzymatic activity and limits ROS production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CPT1B is the muscle-type carnitine palmitoyltransferase I that catalyzes the rate-limiting step of mitochondrial long-chain fatty acid β-oxidation in heart and skeletal muscle by transferring acyl groups from acyl-CoA to carnitine [PMID:12015320, PMID:34330275]. Its enzymatic activity is allosterically inhibited by malonyl-CoA, and a knock-in mouse expressing a malonyl-CoA–insensitive mutant (E3A) shows nearly twofold elevated cardiac fatty acid oxidation with compensatory transcriptional downregulation of FAO genes [PMID:29635338]. Post-translationally, prolyl hydroxylation at P295 by PHD2/3 is required for CPT1B interaction with VDAC1 and for functional long-chain fatty acid oxidation in cardiomyocytes [PMID:34610308]. CPT1B transcription is regulated by a network of activators and repressors—including MEF2A/HDAC5, EZH2-mediated H3K27me3, AR, MITF, ZNF263, and SMAD3—and in sperm mitochondria, TEX44 physically modulates CPT1B activity to limit ROS production, with germ-cell-specific Cpt1b knockout causing mitochondrial sheath defects and impaired sperm motility [PMID:25213552, PMID:31735087, PMID:40849303].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that human CPT1B is a distinct gene at 22qter with its own alternative splicing pattern resolved the question of how muscle-type and liver-type CPT1 isoforms are independently encoded.\",\n      \"evidence\": \"cDNA/genomic sequencing and FISH mapping of human CPT1B\",\n      \"pmids\": [\"9199240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of the intron 13 splice variant (10 aa deletion) not tested enzymatically\", \"Regulatory differences between two CPT1B promoters not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that CPT1B splice variants lack enzymatic activity when expressed in Pichia pastoris ruled out alternative splicing as a mechanism for modulating malonyl-CoA sensitivity, reinforcing that allosteric regulation is the primary control point.\",\n      \"evidence\": \"Heterologous expression in Pichia pastoris with enzymatic activity assay\",\n      \"pmids\": [\"12015320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structural determinants of malonyl-CoA sensitivity not mapped at the residue level\", \"Whether splice variants have non-enzymatic functions not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying MEF2A as a direct transcriptional activator of Cpt1b whose activity is derepressed by exercise-induced HDAC5 phosphorylation and nuclear export established the first defined transcription factor–promoter mechanism for exercise-induced FAO gene upregulation in skeletal muscle.\",\n      \"evidence\": \"ChIP, luciferase promoter assay, MEF2A overexpression in C2C12 myoblasts, mouse treadmill exercise model\",\n      \"pmids\": [\"25213552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MEF2A is sufficient for exercise-induced CPT1B upregulation or acts in combination with other factors\", \"HDAC3 contribution at the CPT1B promoter not dissected independently of HDAC5\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that CpG hypermethylation at the CPT1B promoter blocks USF binding and blunts lipid-responsive CPT1B induction in obese human muscle revealed an epigenetic layer of CPT1B regulation with metabolic disease relevance.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, histone acetylation assays in primary human skeletal muscle cultures from obese vs. lean women\",\n      \"pmids\": [\"26058865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation changes are cause or consequence of obesity not determined\", \"Writers/erasers responsible for CPT1B promoter methylation not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The CPT1B-E3A knock-in mouse provided direct in vivo evidence that malonyl-CoA inhibition is the rate-limiting control point for cardiac FAO, as relieving this inhibition increased FAO ~1.9-fold with compensatory transcriptional feedback.\",\n      \"evidence\": \"CPT1B-E3A knock-in mice, isolated perfused heart FAO assay, multi-omics\",\n      \"pmids\": [\"29635338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chronic loss of malonyl-CoA sensitivity causes cardiac pathology under stress conditions\", \"The identity of the feedback sensor linking FAO flux to CPT1B transcription is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"EZH2-mediated H3K27me3 at the CPT1B promoter was shown to suppress CPT1B transcription during cardiac hypertrophy, establishing a Polycomb-group epigenetic silencing mechanism controlled upstream by mTORC1 and the lncRNA uc.323.\",\n      \"evidence\": \"ChIP for EZH2/H3K27me3, lncRNA microarray, gain/loss-of-function in cardiomyocytes, aortic banding mouse model\",\n      \"pmids\": [\"31735087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EZH2 recruitment is specific to CPT1B or part of a broader FAO gene silencing program\", \"Direct interaction between uc.323 and EZH2 at the CPT1B locus not confirmed by CLIP or similar\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple transcription factors were shown to directly bind the CPT1B promoter—AR as a repressor and miR-138-5p as a post-transcriptional silencer—expanding the regulatory network controlling CPT1B expression in contexts ranging from prostate cancer to NAFLD.\",\n      \"evidence\": \"ChIP and dual-luciferase for AR (prostate cancer cells); dual-luciferase with 3′UTR mutation for miR-138-5p (rat NAFLD model)\",\n      \"pmids\": [\"32648618\", \"32325349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AR-CPT1B axis not validated in non-cancer tissues\", \"Physiological relevance of miR-138-5p regulation of CPT1B outside of the NAFLD model unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that PHD2/3-mediated prolyl hydroxylation at P295 is required for CPT1B–VDAC1 interaction and functional FAO revealed a novel oxygen-sensing post-translational control of mitochondrial fatty acid import.\",\n      \"evidence\": \"Co-IP, CPT1B-P295A mutagenesis, PHD2/3 KO mice, high-fat diet rescue experiments in cardiomyocytes\",\n      \"pmids\": [\"34610308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how P295 hydroxylation promotes VDAC1 binding not resolved\", \"Whether other mitochondrial outer membrane partners are regulated by this hydroxylation is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multi-omic analysis of aged skeletal muscle identified CPT1B as the specific protein whose decline under high-fat diet causes loss of metabolic flexibility, positioning it as the dominant flux controller of FAO in aging.\",\n      \"evidence\": \"Proteomics, lipidomics, mitochondrial function analysis, computational metabolic flux modeling in young vs. aged mice\",\n      \"pmids\": [\"34330275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether restoring CPT1B levels rescues metabolic flexibility in aged muscle not tested\", \"Mechanism of age-specific CPT1B protein decline not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SMAD3 was identified as a direct CPT1B promoter-binding transcription factor downstream of myostatin signaling, linking the myostatin–SMAD3 axis to FAO regulation in skeletal muscle.\",\n      \"evidence\": \"ChIP, CPT1 enzyme activity assay, Mstn knockdown in mouse skeletal muscle\",\n      \"pmids\": [\"36002433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMAD3 acts as activator or repressor at the Cpt1b promoter not fully resolved\", \"Contribution relative to other SMAD isoforms not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MITF was identified as a transcriptional repressor of CPT1B in lung adenocarcinoma, directly linking FAO suppression to cancer stem cell stemness regulation.\",\n      \"evidence\": \"ChIP and dual-luciferase assay confirming MITF binding at CPT1B promoter, FAO and sphere-forming assays\",\n      \"pmids\": [\"38016436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MITF regulation of CPT1B occurs in non-cancer melanocytic or muscle lineages\", \"Downstream metabolic intermediates linking reduced FAO to stemness not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CPT1B was found to interact with KEAP1, and its knockdown reduces NRF2 and induces ferroptosis in pancreatic cancer cells, suggesting a non-canonical role in redox homeostasis beyond its enzymatic function.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, ferroptosis markers, xenograft model\",\n      \"pmids\": [\"38302326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or domain mapping\", \"Whether KEAP1 interaction depends on CPT1B enzymatic activity or is a scaffolding role not determined\", \"Relevance outside pancreatic cancer not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ZNF263 was identified as a transcriptional activator of CPT1B promoting cisplatin resistance through enhanced FAO in lung adenocarcinoma, demonstrating that CPT1B-driven FAO can be co-opted for drug resistance.\",\n      \"evidence\": \"ChIP and dual-luciferase at CPT1B promoter, FAO rate assay, etomoxir rescue\",\n      \"pmids\": [\"39500874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZNF263 regulates CPT1B in normal muscle or heart tissue\", \"Specificity of ZNF263 for CPT1B versus other FAO genes not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TEX44 was discovered to physically interact with CPT1B in sperm mitochondria, directly modulating its enzymatic activity to limit excess ROS from unregulated FAO; germ-cell-specific Cpt1b KO phenocopied TEX44 deficiency, establishing CPT1B as essential for mitochondrial sheath assembly and male fertility.\",\n      \"evidence\": \"Tex44 KO and germ-cell-specific Cpt1b KO mice, purified TEX44 protein modulating CPT1B activity in vitro, Co-IP, human patient exome sequencing\",\n      \"pmids\": [\"40849303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TEX44–CPT1B interaction not defined\", \"Whether TEX44 modulation involves allosteric inhibition or substrate competition unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"AAV-mediated cardiac CPT1B overexpression attenuated pressure-overload-induced hypertrophy and fibrosis, providing direct gain-of-function evidence that maintaining CPT1B levels is cardioprotective.\",\n      \"evidence\": \"AAV gene transfer in neonatal rat cardiomyocytes and transverse aortic constriction mouse model with echocardiography and histology\",\n      \"pmids\": [\"40646338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cardioprotection is solely via increased FAO or involves non-enzymatic CPT1B functions\", \"Long-term effects of sustained CPT1B overexpression not evaluated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of malonyl-CoA inhibition and PHD-mediated hydroxylation effects on CPT1B conformation, how the extensive transcriptional regulatory network is integrated in a tissue- and context-specific manner, and whether non-enzymatic roles (e.g., KEAP1 interaction, scaffolding in sperm mitochondria) represent a general moonlighting function of CPT1B.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length CPT1B with malonyl-CoA or VDAC1\", \"Tissue-specific integration of multiple TF inputs not modeled\", \"Non-enzymatic roles lack structural or reconstitution-level evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 4, 5, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 10, 16, 17]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VDAC1\",\n      \"TEX44\",\n      \"KEAP1\",\n      \"EZH2\",\n      \"MEF2A\",\n      \"HDAC5\",\n      \"SMAD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}