{"gene":"CPT1B","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"CPT1B (M-CPT I) encodes the muscle-type carnitine palmitoyltransferase I isoform responsible for the rate-limiting step in beta-oxidation of long-chain fatty acids in heart and skeletal muscle. When three previously described splice variants were expressed in Pichia pastoris, none had CPT I enzymatic activity, indicating that splice variation of M-CPT I does not modulate malonyl-CoA inhibition of fatty acid oxidation as previously proposed.","method":"Heterologous expression in Pichia pastoris, enzymatic activity assay, genomic/cDNA structural analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic reconstitution in yeast expression system with multiple splice variants tested; foundational structural and functional genomics paper","pmids":["12015320"],"is_preprint":false},{"year":2018,"finding":"Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating cardiac fatty acid oxidation rate. A knock-in mouse expressing CPT1B E3A mutant (reduced malonyl-CoA sensitivity) showed 1.9-fold higher FAO in isolated perfused hearts, along with increased malonylcarnitine, decreased CPT1B protein, and coordinated downregulation of FAO gene mRNA expression as compensatory responses.","method":"Knock-in mouse model, isolated perfused heart FAO measurements, metabolomics, proteomics, transcriptomics","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo knock-in mutagenesis with direct enzymatic/metabolic readout plus multi-omic compensation analysis in single rigorous study","pmids":["29635338"],"is_preprint":false},{"year":2021,"finding":"PHD2/3 (prolyl hydroxylase domain proteins) bind to CPT1B and promote hydroxylation of CPT1B at proline 295 (P295). This P295 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, establishing an oxygen-sensitive regulatory axis for cardiac metabolism.","method":"Co-immunoprecipitation, mutagenesis (P295A knock-in), cardiomyocyte loss-of-function (PHD2/3 knockout mice), rescue experiments, FAO assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding, site-specific mutagenesis with functional rescue, and in vivo genetic model; multiple orthogonal methods in one study","pmids":["34610308"],"is_preprint":false},{"year":2025,"finding":"TEX44 interacts physically with CPT1B to form a mitochondrial glue that anchors adjacent mitochondria and facilitates assembly of the sperm-specific mitochondrial sheath. Purified TEX44 protein modulates CPT1B enzymatic activity in vitro, limiting conversion of long-chain fatty acids (palmitic acid, myristic acid) to acyl-carnitines and thereby reducing ROS production. Loss of TEX44 leads to unregulated FAO, excessive ROS, and oxidative damage to sperm DNA and flagellar structure. Germ cell-specific Cpt1b knockout mice recapitulate TEX44-deficiency phenotypes including mitochondrial sheath defects and reduced sperm motility.","method":"Co-immunoprecipitation, purified protein in vitro enzymatic activity assay, Tex44 knockout mice, germ cell-specific Cpt1b knockout mice, whole-exome sequencing of patients","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified protein, reciprocal genetic validation with two knockout mouse models, and human patient variant data","pmids":["40849303"],"is_preprint":false},{"year":2026,"finding":"CPT1B is crotonylated at lysine 321 (K321cr) during endotoxic shock, and this modification impairs CPT1B enzymatic activity. The crotonyl-transferase P300 promotes K321 crotonylation while CBP normally protects CPT1B from this modification; LPS induces dissociation of CBP from CPT1B and recruitment of P300. K321R mutation prevents crotonylation, alleviates lipid droplet deposition and mitochondrial dysfunction (restored ATP and mitochondrial membrane potential), and protects against endotoxic shock-induced cardiomyopathy in vivo.","method":"Crotonylproteomic mass spectrometry, site-directed mutagenesis (K321R), LC-MS/MS identification of writer enzymes (P300/CBP), AAV9 cardiac-specific overexpression in rats, co-immunoprecipitation, enzymatic activity assays","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific PTM identified by MS, mutagenesis with functional rescue both in vitro and in vivo, writer enzymes identified by IP; single lab but multiple orthogonal methods","pmids":["42209697"],"is_preprint":false},{"year":2014,"finding":"Exercise training increases binding of MEF2A transcription factor to the Cpt1b promoter in mouse skeletal muscle, while decreasing binding of the repressor HDAC5. MEF2A overexpression in C2C12 myoblasts increases Cpt1b mRNA and promoter transcriptional activity, effects suppressed by HDAC5. Exercise induces MEF2A hyperacetylation, increases HDAC5 phosphorylation at Ser259/Ser498, and causes nuclear export of HDAC5, collectively driving CPT1B transcription.","method":"Chromatin immunoprecipitation (ChIP), reporter gene assay (Cpt1b promoter luciferase), MEF2A and HDAC5 overexpression in C2C12 cells, real-time PCR, Western blot, nuclear/cytoplasmic fractionation","journal":"Acta physiologica (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay are orthogonal methods in vivo and in vitro, single lab","pmids":["25213552"],"is_preprint":false},{"year":2019,"finding":"EZH2 binds to the CPT1b promoter via H3K27me3 to repress CPT1b transcription during cardiac hypertrophy. The long noncoding RNA uc.323 protects against hypertrophy partly by interacting with EZH2, preventing CPT1b repression; overexpression of CPT1b blocks uc.323-mediated cardiomyocyte hypertrophy.","method":"Chromatin immunoprecipitation (ChIP), microarray mRNA expression analysis, gain/loss-of-function in cardiomyocytes, CPT1b overexpression rescue experiments, aortic banding mouse model","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms EZH2/H3K27me3 occupancy at CPT1b promoter, functional rescue with CPT1b overexpression; single lab","pmids":["31735087"],"is_preprint":false},{"year":2015,"finding":"In response to lipid exposure, CPT1B gene transcription in skeletal muscle is regulated by epigenetic modifications including CpG methylation, H3/H4 histone acetylation, and transcription factor occupancy (PPARδ and HNF4α) at the CPT1B promoter. Methylation of specific CpG sites blocks binding of the transcription factor USF (upstream stimulatory factor), suggesting a causal mechanism for the blunted CPT1B induction seen in severely obese individuals.","method":"Primary human skeletal muscle cultures, bisulfite sequencing (CpG methylation), ChIP (histone acetylation, transcription factor occupancy), RT-PCR, transcription factor binding assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple epigenetic methods plus functional binding assay; single lab","pmids":["26058865"],"is_preprint":false},{"year":2020,"finding":"Androgen receptor (AR) regulates CPT1B transcriptional activity via specific binding sites in the CPT1B promoter, as confirmed by dual luciferase reporter assay and ChIP assay in prostate cancer cells. AR inhibition affects CPT1B expression; CPT1B overexpression in enzalutamide-resistant C4-2R cells increases AKT expression and phosphorylation, promoting drug resistance.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), JASPAR binding site analysis, stable knockdown/overexpression cell lines, CCK-8 assay","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase and ChIP are orthogonal methods confirming AR-CPT1B promoter interaction; single lab","pmids":["32648618"],"is_preprint":false},{"year":2024,"finding":"ZNF263 transcription factor binds to the CPT1B promoter to activate its transcription, thereby enhancing fatty acid beta-oxidation and promoting cisplatin resistance in lung adenocarcinoma cells. This was confirmed by dual-luciferase reporter assay and ChIP assay.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, FAO rate measurement, IC50 assay (CCK-8)","journal":"The pharmacogenomics journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter provide orthogonal evidence for direct transcriptional regulation; single lab","pmids":["39500874"],"is_preprint":false},{"year":2023,"finding":"MITF transcription factor binds the CPT1B promoter and inhibits its transcription in lung adenocarcinoma cells, reducing fatty acid beta-oxidation and suppressing cancer stem cell stemness. Confirmed by dual-luciferase reporter assay and ChIP assay.","method":"Dual-luciferase reporter assay, ChIP assay, qRT-PCR, Western blot, sphere-forming assay, FAO measurement","journal":"Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter as orthogonal methods for direct transcriptional regulation; single lab","pmids":["38016436"],"is_preprint":false},{"year":2025,"finding":"STAT3 directly interacts with CPT1B in pancreatic cancer stem cells, as demonstrated by chromatin immunoprecipitation assay. Manipulation of STAT3 expression (overexpression or siRNA knockdown) alters CPT1B mRNA and protein levels. Quercetin inhibits CPT1B expression via the STAT3 signaling pathway, affecting lipid metabolism.","method":"Chromatin immunoprecipitation (ChIP), STAT3 siRNA knockdown and overexpression, qRT-PCR, Western blot, CCK-8, sphere formation assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP experiment with limited mechanistic follow-up; single lab","pmids":["40412371"],"is_preprint":false},{"year":2019,"finding":"In LRP6 cardiac-specific knockout mice, CPT1B protein is sharply decreased coincident with Drp1 activation, and Drp1 inhibitor restores CPT1B expression. In cardiomyocytes in vitro, c-Myc (but not CTCF) was identified as a transcriptional regulator of CPT1B expression and lipid accumulation.","method":"Cardiac-specific LRP6 knockout mice, Drp1 inhibitor treatment, GC-FID/MS fatty acid analysis, ChIP-like transcription factor binding assay, c-Myc overexpression in cardiomyocytes","journal":"Cell and tissue research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — c-Myc regulation identified by in vitro overexpression only; indirect pathway placement via Drp1 inhibitor; single lab, limited mechanistic depth","pmids":["31811407"],"is_preprint":false},{"year":2013,"finding":"CB1 (cannabinoid receptor 1) is upstream of CPT1B in porcine intramuscular adipocytes: CB1 agonist (Δ9-THC) decreased CPT1B mRNA and increased lipid accumulation, while CB1 antagonist (SR141716) increased CPT1B mRNA and decreased lipid accumulation. CPT1 antagonist etomoxir did not affect CB1 expression, confirming CB1 is upstream of CPT1B. PPARα expression was co-regulated with CPT1B.","method":"Pharmacological agonist/antagonist treatment of porcine intramuscular adipocytes, mRNA expression analysis, lipid accumulation assay","journal":"Animal genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological epistasis in primary cells without direct binding or promoter assays; single lab","pmids":["23914904"],"is_preprint":false},{"year":2022,"finding":"SMAD3, a transcription factor downstream of myostatin (Mstn) signaling, directly binds to the Cpt1b promoter as shown by chromatin immunoprecipitation. Mstn knockdown upregulates Cpt1b expression and CPT1 enzyme activity in skeletal muscle, promoting fatty acid beta-oxidation.","method":"Chromatin immunoprecipitation (ChIP) for SMAD3 binding to Cpt1b promoter, RNA interference (Mstn knockdown mice), CPT1 enzyme activity assay, fatty acid composition analysis","journal":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct SMAD3 binding to Cpt1b promoter, combined with enzymatic activity assay and in vivo model; single lab","pmids":["36002433"],"is_preprint":false},{"year":2021,"finding":"In proximal tubular epithelial cells, ANXA1 silencing suppresses phosphorylation of AMPK at Thr172 via FPR2/ALX signaling, leading to decreased PPARα and CPT1B expression and increased lipid accumulation. This places CPT1B downstream of the ANXA1/FPR2/AMPK/PPARα axis in renal lipid metabolism.","method":"siRNA knockdown of ANXA1 in human PTECs, phospho-AMPK Western blot, CPT1B expression measurement, lipid accumulation assay, diabetic mouse model with ANXA1 deletion","journal":"Diabetes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by knockdown and expression correlation without direct CPT1B mechanistic interrogation; single lab","pmids":["34103347"],"is_preprint":false},{"year":2024,"finding":"CPT1B interacts with KEAP1 (Kelch-like ECH-associated protein 1), and CPT1B knockdown leads to decreased NRF2 expression and induction of ferroptosis in pancreatic cancer cells, establishing a CPT1B-KEAP1-NRF2 regulatory connection that maintains redox homeostasis.","method":"Co-immunoprecipitation (CPT1B-KEAP1 interaction), CPT1B siRNA knockdown, NRF2 expression measurement, ROS/lipid peroxidation/glutathione assays, flow cytometry for ferroptosis markers, xenograft model","journal":"Surgery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP identifies CPT1B-KEAP1 interaction, functional ferroptosis phenotype confirmed in vitro and in vivo; single lab","pmids":["38302326"],"is_preprint":false},{"year":2026,"finding":"BHLHE40 recruits HDAC1 to the CPT1B promoter (confirmed by CUT&Tag) to transcriptionally repress CPT1B expression, impairing NRF2 signaling and driving ferroptosis in E. coli-infected endometrial cells. Overexpression of CPT1B reactivates NRF2 and its downstream targets to inhibit ferroptosis.","method":"CUT&Tag, RNA-sequencing, CPT1B overexpression rescue, NRF2 inhibitor epistasis, siRNA knockdown of BHLHE40, lipid peroxidation/glutathione/Fe2+ assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag plus transcriptomics provide orthogonal evidence for direct BHLHE40-HDAC1-CPT1B promoter regulation, with functional rescue; single lab","pmids":["42128070"],"is_preprint":false},{"year":2025,"finding":"AAV-mediated cardiac overexpression of CPT1B in neonatal rat cardiomyocytes attenuates phenylephrine-induced hypertrophy and decreases mitochondrial ROS generation. In mice subjected to transverse aortic constriction (TAC), cardiac CPT1B overexpression attenuates cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction in vivo.","method":"AAV gene transfer to neonatal rat cardiomyocytes and mouse hearts, phenylephrine-induced hypertrophy model, TAC pressure overload model, mitochondrial ROS measurement, echocardiography, histology","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gene transfer with defined phenotypic readouts in both in vitro and in vivo models; single lab","pmids":["40646338"],"is_preprint":false},{"year":2024,"finding":"cpt1b regulates cardiomyocyte proliferation during zebrafish development through modulation of glutamine synthetase. Knockout of cpt1b impairs cardiomyocyte proliferation, while cardiomyocyte-specific overexpression promotes it. Pharmacological studies and RNA sequencing identified glutamine synthetase as a key downstream effector.","method":"cpt1b knockout zebrafish, cardiomyocyte-specific cpt1b overexpression, RNA sequencing, pharmacological glutamine synthetase inhibition","journal":"Journal of cardiovascular development and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function genetic models in zebrafish with RNA-seq pathway placement; single lab","pmids":["39590187"],"is_preprint":false},{"year":2020,"finding":"miR-138-5p directly targets CPT1B mRNA: miR-138-5p mimic reduces CPT1B expression and luciferase activity from a wild-type CPT1B 3'UTR reporter, while miR-138-5p inhibitor increases CPT1B expression. When CPT1B is mutated at the predicted binding site, miR-138-5p can no longer regulate luciferase activity, confirming direct targeting.","method":"Dual-luciferase reporter assay with wild-type and mutant CPT1B 3'UTR, miR-138-5p mimic/inhibitor transfection, RT-PCR","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase with mutation confirms direct miRNA-mRNA interaction; single lab","pmids":["32325349"],"is_preprint":false},{"year":2016,"finding":"Cardiac-specific CPT1B silencing (via intramyocardial lentiviral injection) in obese mice on a high-fat diet protected against HFD-induced cardiac remodeling by decreasing heart weight/tibial length ratio, improving left ventricular ejection fraction and fractional shortening, reducing intramyocardial ROS production, and aggravating myocardial lipid accumulation, indicating CPT1B-driven FAO is a source of ROS in the obese heart.","method":"Lentiviral cardiac-specific CPT1B knockdown in mice, HFD obesity model, echocardiography, histology, biochemical parameters, ROS measurement","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cardiac-specific loss-of-function with defined functional and metabolic phenotypic readouts; single lab","pmids":["27804274"],"is_preprint":false},{"year":2025,"finding":"PPARG activation by the compound DHDK upregulates CPT1B expression, enhancing fatty acid beta-oxidation (FAO) in cardiomyocytes. This protective effect is abolished by inhibition of either PPARG or CPT1B, placing CPT1B downstream of PPARG in the cardioprotective PPARG-CPT1B-FAO axis.","method":"Molecular docking, lipidomics, qPCR, Western blot, CCK-8, flow cytometry, pharmacological inhibition of PPARG and CPT1B, in vivo rat model","journal":"Pharmaceuticals (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by pharmacological inhibition without direct CPT1B promoter or binding studies; single lab","pmids":["41305001"],"is_preprint":false}],"current_model":"CPT1B (muscle-type carnitine palmitoyltransferase 1) is the rate-limiting enzyme for mitochondrial long-chain fatty acid beta-oxidation in heart and skeletal muscle, catalyzing transfer of acyl groups to carnitine; its activity is allosterically inhibited by malonyl-CoA, it is post-translationally regulated by PHD2/3-mediated proline-295 hydroxylation (required for interaction with VDAC1) and by P300/CBP-mediated lysine-321 crotonylation (which impairs activity), and its transcription is controlled by multiple factors including MEF2A/HDAC5, EZH2/H3K27me3, AR, ZNF263, MITF, SMAD3, and epigenetic CpG methylation; in sperm, CPT1B activity is modulated by its binding partner TEX44 to balance FAO and ROS production during mitochondrial sheath assembly."},"narrative":{"mechanistic_narrative":"CPT1B is the muscle-type carnitine palmitoyltransferase I that catalyzes the rate-limiting, malonyl-CoA-inhibited step of mitochondrial long-chain fatty acid beta-oxidation (FAO) in heart and skeletal muscle [PMID:12015320, PMID:29635338]. Its malonyl-CoA sensitivity sets cardiac FAO flux: a knock-in mouse with reduced sensitivity raises FAO ~1.9-fold and triggers compensatory downregulation of FAO genes [PMID:29635338]. CPT1B activity is further tuned by post-translational modification at the protein level — oxygen-dependent PHD2/3-mediated proline-295 hydroxylation is required for its interaction with VDAC1 and for LCFA oxidation in cardiomyocytes [PMID:34610308], while P300-mediated lysine-321 crotonylation (opposed by CBP) impairs activity and promotes lipid deposition and mitochondrial dysfunction during endotoxic shock [PMID:42209697]. CPT1B transcription is controlled by a broad set of regulators across tissues, including the MEF2A/HDAC5 axis driven by exercise [PMID:25213552], EZH2/H3K27me3-mediated repression [PMID:31735087], BHLHE40/HDAC1 repression [PMID:42128070], and additional factors such as SMAD3 [PMID:36002433], ZNF263, MITF, and androgen receptor in cancer contexts [PMID:32648618, PMID:39500874, PMID:38016436], with CpG methylation and PPARδ/HNF4α/USF occupancy shaping its lipid-responsive induction in skeletal muscle [PMID:26058865]. Functionally, CPT1B-driven FAO is a regulated source of mitochondrial ROS: silencing it protects the obese heart from remodeling while aggravating lipid accumulation [PMID:27804274], and in sperm its binding partner TEX44 both anchors mitochondria into the sheath and restrains CPT1B activity to limit FAO-derived ROS, with germ-cell-specific Cpt1b loss causing sheath defects and reduced motility [PMID:40849303]. Through a KEAP1 interaction that sustains NRF2 [PMID:38302326] and roles in cardiomyocyte hypertrophy and proliferation [PMID:40646338, PMID:39590187], CPT1B links lipid catabolism to redox homeostasis and cell fate.","teleology":[{"year":2002,"claim":"Established CPT1B as the muscle isoform catalyzing the rate-limiting step of long-chain FAO and showed that its splice variants are catalytically inactive, ruling out splicing as a mechanism for tuning malonyl-CoA inhibition.","evidence":"Heterologous expression of splice variants in Pichia pastoris with enzymatic activity assays and genomic/cDNA analysis","pmids":["12015320"],"confidence":"High","gaps":["Did not define the physiological regulators of malonyl-CoA sensitivity","No structural model of the active enzyme"]},{"year":2014,"claim":"Showed that exercise drives CPT1B transcription through MEF2A recruitment and HDAC5 derepression, linking physical activity to muscle FAO capacity.","evidence":"ChIP, Cpt1b promoter luciferase reporters, MEF2A/HDAC5 overexpression in C2C12 cells, and fractionation in mouse muscle","pmids":["25213552"],"confidence":"Medium","gaps":["Does not establish whether MEF2A/HDAC5 control CPT1B in non-muscle tissues","Upstream signals coupling exercise to HDAC5 phosphorylation only partially defined"]},{"year":2015,"claim":"Identified epigenetic control of CPT1B by CpG methylation and transcription factor occupancy, providing a mechanism for blunted FAO gene induction in obesity.","evidence":"Bisulfite sequencing, ChIP, and transcription factor binding assays in primary human skeletal muscle cultures","pmids":["26058865"],"confidence":"Medium","gaps":["Causal link between specific methylated sites and clinical phenotype is correlative","Did not test methylation editing in vivo"]},{"year":2016,"claim":"Demonstrated that CPT1B-driven FAO is a source of cardiac ROS, since cardiac CPT1B silencing protected obese hearts from remodeling at the cost of lipid accumulation.","evidence":"Cardiac-specific lentiviral CPT1B knockdown in high-fat-diet mice with echocardiography, histology, and ROS measurement","pmids":["27804274"],"confidence":"Medium","gaps":["Apparently opposite to later studies where CPT1B overexpression is cardioprotective — context dependence unresolved","Did not define how FAO flux generates ROS"]},{"year":2018,"claim":"Proved that malonyl-CoA inhibition of CPT1B sets the cardiac FAO rate in vivo and that loss of inhibition is buffered by transcriptional compensation.","evidence":"CPT1B E3A malonyl-CoA-insensitive knock-in mouse with perfused-heart FAO, metabolomics, proteomics, and transcriptomics","pmids":["29635338"],"confidence":"High","gaps":["Mechanism of the compensatory FAO gene downregulation not identified","Long-term consequences for cardiac function not assessed"]},{"year":2021,"claim":"Revealed an oxygen-sensitive post-translational switch in which PHD2/3 hydroxylate CPT1B at Pro295 to enable VDAC1 binding and LCFA oxidation.","evidence":"Co-IP, P295A mutagenesis with functional rescue, and PHD2/3-knockout cardiomyocytes with FAO assays","pmids":["34610308"],"confidence":"High","gaps":["How VDAC1 binding mechanistically supports FAO is unresolved","Stoichiometry and dynamics of hydroxylation under physiological oxygen tension not defined"]},{"year":2019,"claim":"Added EZH2/H3K27me3 repression of CPT1B as a node in cardiac hypertrophy, antagonized by lncRNA uc.323.","evidence":"ChIP, gain/loss-of-function in cardiomyocytes, CPT1B overexpression rescue, and aortic banding mice","pmids":["31735087"],"confidence":"Medium","gaps":["How uc.323 directs EZH2 away from the CPT1B locus not detailed","Single lab"]},{"year":2022,"claim":"Placed CPT1B downstream of myostatin signaling, with SMAD3 directly binding its promoter to restrain muscle FAO.","evidence":"ChIP for SMAD3 promoter binding, Mstn-knockdown mice, and CPT1 activity/fatty acid composition assays","pmids":["36002433"],"confidence":"Medium","gaps":["Whether SMAD3 acts as direct repressor or via cofactors unclear","Single lab"]},{"year":2024,"claim":"Connected CPT1B to redox control via a KEAP1 interaction sustaining NRF2 and protecting cancer cells from ferroptosis, and identified divergent cancer transcriptional regulators (ZNF263 activating, MITF repressing).","evidence":"Co-IP, siRNA knockdown with ferroptosis assays and xenografts; dual-luciferase and ChIP in lung adenocarcinoma cells","pmids":["38302326","39500874","38016436"],"confidence":"Medium","gaps":["Whether KEAP1 binding depends on CPT1B catalytic activity unknown","Reciprocal validation of KEAP1 interaction limited"]},{"year":2025,"claim":"Defined a non-metabolic structural and rheostat role in sperm, where TEX44 anchors mitochondria into the sheath and restrains CPT1B activity to limit FAO-derived ROS.","evidence":"Co-IP, purified-protein in vitro activity assays, Tex44 and germ-cell-specific Cpt1b knockout mice, and patient whole-exome sequencing","pmids":["40849303"],"confidence":"High","gaps":["How TEX44 binding biochemically inhibits CPT1B not resolved","Whether the mitochondrial-glue role requires CPT1B enzymatic function unclear"]},{"year":2026,"claim":"Identified lysine-321 crotonylation, written by P300 and protected by CBP, as a disease-associated PTM that impairs CPT1B and drives endotoxic cardiomyopathy.","evidence":"Crotonylproteomics, K321R mutagenesis with rescue, IP-based writer identification, and AAV9 cardiac overexpression in rats","pmids":["42209697"],"confidence":"High","gaps":["Eraser enzyme for K321cr not identified","Crosstalk with Pro295 hydroxylation not examined"]},{"year":null,"claim":"How the many transcriptional, epigenetic, and post-translational inputs are integrated to set CPT1B activity in a given tissue, and whether its enzymatic versus scaffolding/redox roles are separable, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking Pro295 hydroxylation, K321 crotonylation, and VDAC1/TEX44/KEAP1 binding","Tissue-specific selection among the documented transcriptional regulators undefined","Reconciliation of protective vs. ROS-generating roles of CPT1B-driven FAO across heart contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,14,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,3,4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,7,8,9,10,14,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,21]}],"complexes":[],"partners":["VDAC1","PHD2","PHD3","TEX44","KEAP1","P300","CBP"],"other_free_text":[]}},"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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transfer","date":"2024-10-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.30.615965","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32121,"output_tokens":6389,"usd":0.096099,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15410,"output_tokens":3975,"usd":0.088212,"stage2_stop_reason":"end_turn"},"total_usd":0.184311,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CPT1B (M-CPT I) encodes the muscle-type carnitine palmitoyltransferase I isoform responsible for the rate-limiting step in beta-oxidation of long-chain fatty acids in heart and skeletal muscle. When three previously described splice variants were expressed in Pichia pastoris, none had CPT I enzymatic activity, indicating that splice variation of M-CPT I does not modulate malonyl-CoA inhibition of fatty acid oxidation as previously proposed.\",\n      \"method\": \"Heterologous expression in Pichia pastoris, enzymatic activity assay, genomic/cDNA structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic reconstitution in yeast expression system with multiple splice variants tested; foundational structural and functional genomics paper\",\n      \"pmids\": [\"12015320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating cardiac fatty acid oxidation rate. A knock-in mouse expressing CPT1B E3A mutant (reduced malonyl-CoA sensitivity) showed 1.9-fold higher FAO in isolated perfused hearts, along with increased malonylcarnitine, decreased CPT1B protein, and coordinated downregulation of FAO gene mRNA expression as compensatory responses.\",\n      \"method\": \"Knock-in mouse model, isolated perfused heart FAO measurements, metabolomics, proteomics, transcriptomics\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo knock-in mutagenesis with direct enzymatic/metabolic readout plus multi-omic compensation analysis in single rigorous study\",\n      \"pmids\": [\"29635338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHD2/3 (prolyl hydroxylase domain proteins) bind to CPT1B and promote hydroxylation of CPT1B at proline 295 (P295). This P295 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, establishing an oxygen-sensitive regulatory axis for cardiac metabolism.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (P295A knock-in), cardiomyocyte loss-of-function (PHD2/3 knockout mice), rescue experiments, FAO assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding, site-specific mutagenesis with functional rescue, and in vivo genetic model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"34610308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEX44 interacts physically with CPT1B to form a mitochondrial glue that anchors adjacent mitochondria and facilitates assembly of the sperm-specific mitochondrial sheath. Purified TEX44 protein modulates CPT1B enzymatic activity in vitro, limiting conversion of long-chain fatty acids (palmitic acid, myristic acid) to acyl-carnitines and thereby reducing ROS production. Loss of TEX44 leads to unregulated FAO, excessive ROS, and oxidative damage to sperm DNA and flagellar structure. Germ cell-specific Cpt1b knockout mice recapitulate TEX44-deficiency phenotypes including mitochondrial sheath defects and reduced sperm motility.\",\n      \"method\": \"Co-immunoprecipitation, purified protein in vitro enzymatic activity assay, Tex44 knockout mice, germ cell-specific Cpt1b knockout mice, whole-exome sequencing of patients\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified protein, reciprocal genetic validation with two knockout mouse models, and human patient variant data\",\n      \"pmids\": [\"40849303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CPT1B is crotonylated at lysine 321 (K321cr) during endotoxic shock, and this modification impairs CPT1B enzymatic activity. The crotonyl-transferase P300 promotes K321 crotonylation while CBP normally protects CPT1B from this modification; LPS induces dissociation of CBP from CPT1B and recruitment of P300. K321R mutation prevents crotonylation, alleviates lipid droplet deposition and mitochondrial dysfunction (restored ATP and mitochondrial membrane potential), and protects against endotoxic shock-induced cardiomyopathy in vivo.\",\n      \"method\": \"Crotonylproteomic mass spectrometry, site-directed mutagenesis (K321R), LC-MS/MS identification of writer enzymes (P300/CBP), AAV9 cardiac-specific overexpression in rats, co-immunoprecipitation, enzymatic activity assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific PTM identified by MS, mutagenesis with functional rescue both in vitro and in vivo, writer enzymes identified by IP; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"42209697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Exercise training increases binding of MEF2A transcription factor to the Cpt1b promoter in mouse skeletal muscle, while decreasing binding of the repressor HDAC5. MEF2A overexpression in C2C12 myoblasts increases Cpt1b mRNA and promoter transcriptional activity, effects suppressed by HDAC5. Exercise induces MEF2A hyperacetylation, increases HDAC5 phosphorylation at Ser259/Ser498, and causes nuclear export of HDAC5, collectively driving CPT1B transcription.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter gene assay (Cpt1b promoter luciferase), MEF2A and HDAC5 overexpression in C2C12 cells, real-time PCR, Western blot, nuclear/cytoplasmic fractionation\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay are orthogonal methods in vivo and in vitro, single lab\",\n      \"pmids\": [\"25213552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EZH2 binds to the CPT1b promoter via H3K27me3 to repress CPT1b transcription during cardiac hypertrophy. The long noncoding RNA uc.323 protects against hypertrophy partly by interacting with EZH2, preventing CPT1b repression; overexpression of CPT1b blocks uc.323-mediated cardiomyocyte hypertrophy.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), microarray mRNA expression analysis, gain/loss-of-function in cardiomyocytes, CPT1b overexpression rescue experiments, aortic banding mouse model\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms EZH2/H3K27me3 occupancy at CPT1b promoter, functional rescue with CPT1b overexpression; single lab\",\n      \"pmids\": [\"31735087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In response to lipid exposure, CPT1B gene transcription in skeletal muscle is regulated by epigenetic modifications including CpG methylation, H3/H4 histone acetylation, and transcription factor occupancy (PPARδ and HNF4α) at the CPT1B promoter. Methylation of specific CpG sites blocks binding of the transcription factor USF (upstream stimulatory factor), suggesting a causal mechanism for the blunted CPT1B induction seen in severely obese individuals.\",\n      \"method\": \"Primary human skeletal muscle cultures, bisulfite sequencing (CpG methylation), ChIP (histone acetylation, transcription factor occupancy), RT-PCR, transcription factor binding assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple epigenetic methods plus functional binding assay; single lab\",\n      \"pmids\": [\"26058865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Androgen receptor (AR) regulates CPT1B transcriptional activity via specific binding sites in the CPT1B promoter, as confirmed by dual luciferase reporter assay and ChIP assay in prostate cancer cells. AR inhibition affects CPT1B expression; CPT1B overexpression in enzalutamide-resistant C4-2R cells increases AKT expression and phosphorylation, promoting drug resistance.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), JASPAR binding site analysis, stable knockdown/overexpression cell lines, CCK-8 assay\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase and ChIP are orthogonal methods confirming AR-CPT1B promoter interaction; single lab\",\n      \"pmids\": [\"32648618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF263 transcription factor binds to the CPT1B promoter to activate its transcription, thereby enhancing fatty acid beta-oxidation and promoting cisplatin resistance in lung adenocarcinoma cells. This was confirmed by dual-luciferase reporter assay and ChIP assay.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, FAO rate measurement, IC50 assay (CCK-8)\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter provide orthogonal evidence for direct transcriptional regulation; single lab\",\n      \"pmids\": [\"39500874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MITF transcription factor binds the CPT1B promoter and inhibits its transcription in lung adenocarcinoma cells, reducing fatty acid beta-oxidation and suppressing cancer stem cell stemness. Confirmed by dual-luciferase reporter assay and ChIP assay.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP assay, qRT-PCR, Western blot, sphere-forming assay, FAO measurement\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter as orthogonal methods for direct transcriptional regulation; single lab\",\n      \"pmids\": [\"38016436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAT3 directly interacts with CPT1B in pancreatic cancer stem cells, as demonstrated by chromatin immunoprecipitation assay. Manipulation of STAT3 expression (overexpression or siRNA knockdown) alters CPT1B mRNA and protein levels. Quercetin inhibits CPT1B expression via the STAT3 signaling pathway, affecting lipid metabolism.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), STAT3 siRNA knockdown and overexpression, qRT-PCR, Western blot, CCK-8, sphere formation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP experiment with limited mechanistic follow-up; single lab\",\n      \"pmids\": [\"40412371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In LRP6 cardiac-specific knockout mice, CPT1B protein is sharply decreased coincident with Drp1 activation, and Drp1 inhibitor restores CPT1B expression. In cardiomyocytes in vitro, c-Myc (but not CTCF) was identified as a transcriptional regulator of CPT1B expression and lipid accumulation.\",\n      \"method\": \"Cardiac-specific LRP6 knockout mice, Drp1 inhibitor treatment, GC-FID/MS fatty acid analysis, ChIP-like transcription factor binding assay, c-Myc overexpression in cardiomyocytes\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — c-Myc regulation identified by in vitro overexpression only; indirect pathway placement via Drp1 inhibitor; single lab, limited mechanistic depth\",\n      \"pmids\": [\"31811407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CB1 (cannabinoid receptor 1) is upstream of CPT1B in porcine intramuscular adipocytes: CB1 agonist (Δ9-THC) decreased CPT1B mRNA and increased lipid accumulation, while CB1 antagonist (SR141716) increased CPT1B mRNA and decreased lipid accumulation. CPT1 antagonist etomoxir did not affect CB1 expression, confirming CB1 is upstream of CPT1B. PPARα expression was co-regulated with CPT1B.\",\n      \"method\": \"Pharmacological agonist/antagonist treatment of porcine intramuscular adipocytes, mRNA expression analysis, lipid accumulation assay\",\n      \"journal\": \"Animal genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological epistasis in primary cells without direct binding or promoter assays; single lab\",\n      \"pmids\": [\"23914904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMAD3, a transcription factor downstream of myostatin (Mstn) signaling, directly binds to the Cpt1b promoter as shown by chromatin immunoprecipitation. Mstn knockdown upregulates Cpt1b expression and CPT1 enzyme activity in skeletal muscle, promoting fatty acid beta-oxidation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for SMAD3 binding to Cpt1b promoter, RNA interference (Mstn knockdown mice), CPT1 enzyme activity assay, fatty acid composition analysis\",\n      \"journal\": \"Sheng wu gong cheng xue bao = Chinese journal of biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct SMAD3 binding to Cpt1b promoter, combined with enzymatic activity assay and in vivo model; single lab\",\n      \"pmids\": [\"36002433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In proximal tubular epithelial cells, ANXA1 silencing suppresses phosphorylation of AMPK at Thr172 via FPR2/ALX signaling, leading to decreased PPARα and CPT1B expression and increased lipid accumulation. This places CPT1B downstream of the ANXA1/FPR2/AMPK/PPARα axis in renal lipid metabolism.\",\n      \"method\": \"siRNA knockdown of ANXA1 in human PTECs, phospho-AMPK Western blot, CPT1B expression measurement, lipid accumulation assay, diabetic mouse model with ANXA1 deletion\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by knockdown and expression correlation without direct CPT1B mechanistic interrogation; single lab\",\n      \"pmids\": [\"34103347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT1B interacts with KEAP1 (Kelch-like ECH-associated protein 1), and CPT1B knockdown leads to decreased NRF2 expression and induction of ferroptosis in pancreatic cancer cells, establishing a CPT1B-KEAP1-NRF2 regulatory connection that maintains redox homeostasis.\",\n      \"method\": \"Co-immunoprecipitation (CPT1B-KEAP1 interaction), CPT1B siRNA knockdown, NRF2 expression measurement, ROS/lipid peroxidation/glutathione assays, flow cytometry for ferroptosis markers, xenograft model\",\n      \"journal\": \"Surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP identifies CPT1B-KEAP1 interaction, functional ferroptosis phenotype confirmed in vitro and in vivo; single lab\",\n      \"pmids\": [\"38302326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BHLHE40 recruits HDAC1 to the CPT1B promoter (confirmed by CUT&Tag) to transcriptionally repress CPT1B expression, impairing NRF2 signaling and driving ferroptosis in E. coli-infected endometrial cells. Overexpression of CPT1B reactivates NRF2 and its downstream targets to inhibit ferroptosis.\",\n      \"method\": \"CUT&Tag, RNA-sequencing, CPT1B overexpression rescue, NRF2 inhibitor epistasis, siRNA knockdown of BHLHE40, lipid peroxidation/glutathione/Fe2+ assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag plus transcriptomics provide orthogonal evidence for direct BHLHE40-HDAC1-CPT1B promoter regulation, with functional rescue; single lab\",\n      \"pmids\": [\"42128070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AAV-mediated cardiac overexpression of CPT1B in neonatal rat cardiomyocytes attenuates phenylephrine-induced hypertrophy and decreases mitochondrial ROS generation. In mice subjected to transverse aortic constriction (TAC), cardiac CPT1B overexpression attenuates cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction in vivo.\",\n      \"method\": \"AAV gene transfer to neonatal rat cardiomyocytes and mouse hearts, phenylephrine-induced hypertrophy model, TAC pressure overload model, mitochondrial ROS measurement, echocardiography, histology\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene transfer with defined phenotypic readouts in both in vitro and in vivo models; single lab\",\n      \"pmids\": [\"40646338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"cpt1b regulates cardiomyocyte proliferation during zebrafish development through modulation of glutamine synthetase. Knockout of cpt1b impairs cardiomyocyte proliferation, while cardiomyocyte-specific overexpression promotes it. Pharmacological studies and RNA sequencing identified glutamine synthetase as a key downstream effector.\",\n      \"method\": \"cpt1b knockout zebrafish, cardiomyocyte-specific cpt1b overexpression, RNA sequencing, pharmacological glutamine synthetase inhibition\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function genetic models in zebrafish with RNA-seq pathway placement; single lab\",\n      \"pmids\": [\"39590187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-138-5p directly targets CPT1B mRNA: miR-138-5p mimic reduces CPT1B expression and luciferase activity from a wild-type CPT1B 3'UTR reporter, while miR-138-5p inhibitor increases CPT1B expression. When CPT1B is mutated at the predicted binding site, miR-138-5p can no longer regulate luciferase activity, confirming direct targeting.\",\n      \"method\": \"Dual-luciferase reporter assay with wild-type and mutant CPT1B 3'UTR, miR-138-5p mimic/inhibitor transfection, RT-PCR\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase with mutation confirms direct miRNA-mRNA interaction; single lab\",\n      \"pmids\": [\"32325349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cardiac-specific CPT1B silencing (via intramyocardial lentiviral injection) in obese mice on a high-fat diet protected against HFD-induced cardiac remodeling by decreasing heart weight/tibial length ratio, improving left ventricular ejection fraction and fractional shortening, reducing intramyocardial ROS production, and aggravating myocardial lipid accumulation, indicating CPT1B-driven FAO is a source of ROS in the obese heart.\",\n      \"method\": \"Lentiviral cardiac-specific CPT1B knockdown in mice, HFD obesity model, echocardiography, histology, biochemical parameters, ROS measurement\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cardiac-specific loss-of-function with defined functional and metabolic phenotypic readouts; single lab\",\n      \"pmids\": [\"27804274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPARG activation by the compound DHDK upregulates CPT1B expression, enhancing fatty acid beta-oxidation (FAO) in cardiomyocytes. This protective effect is abolished by inhibition of either PPARG or CPT1B, placing CPT1B downstream of PPARG in the cardioprotective PPARG-CPT1B-FAO axis.\",\n      \"method\": \"Molecular docking, lipidomics, qPCR, Western blot, CCK-8, flow cytometry, pharmacological inhibition of PPARG and CPT1B, in vivo rat model\",\n      \"journal\": \"Pharmaceuticals (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by pharmacological inhibition without direct CPT1B promoter or binding studies; single lab\",\n      \"pmids\": [\"41305001\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPT1B (muscle-type carnitine palmitoyltransferase 1) is the rate-limiting enzyme for mitochondrial long-chain fatty acid beta-oxidation in heart and skeletal muscle, catalyzing transfer of acyl groups to carnitine; its activity is allosterically inhibited by malonyl-CoA, it is post-translationally regulated by PHD2/3-mediated proline-295 hydroxylation (required for interaction with VDAC1) and by P300/CBP-mediated lysine-321 crotonylation (which impairs activity), and its transcription is controlled by multiple factors including MEF2A/HDAC5, EZH2/H3K27me3, AR, ZNF263, MITF, SMAD3, and epigenetic CpG methylation; in sperm, CPT1B activity is modulated by its binding partner TEX44 to balance FAO and ROS production during mitochondrial sheath assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPT1B is the muscle-type carnitine palmitoyltransferase I that catalyzes the rate-limiting, malonyl-CoA-inhibited step of mitochondrial long-chain fatty acid beta-oxidation (FAO) in heart and skeletal muscle [#0, #1]. Its malonyl-CoA sensitivity sets cardiac FAO flux: a knock-in mouse with reduced sensitivity raises FAO ~1.9-fold and triggers compensatory downregulation of FAO genes [#1]. CPT1B activity is further tuned by post-translational modification at the protein level — oxygen-dependent PHD2/3-mediated proline-295 hydroxylation is required for its interaction with VDAC1 and for LCFA oxidation in cardiomyocytes [#2], while P300-mediated lysine-321 crotonylation (opposed by CBP) impairs activity and promotes lipid deposition and mitochondrial dysfunction during endotoxic shock [#4]. CPT1B transcription is controlled by a broad set of regulators across tissues, including the MEF2A/HDAC5 axis driven by exercise [#5], EZH2/H3K27me3-mediated repression [#6], BHLHE40/HDAC1 repression [#17], and additional factors such as SMAD3 [#14], ZNF263, MITF, and androgen receptor in cancer contexts [#8, #9, #10], with CpG methylation and PPARδ/HNF4α/USF occupancy shaping its lipid-responsive induction in skeletal muscle [#7]. Functionally, CPT1B-driven FAO is a regulated source of mitochondrial ROS: silencing it protects the obese heart from remodeling while aggravating lipid accumulation [#21], and in sperm its binding partner TEX44 both anchors mitochondria into the sheath and restrains CPT1B activity to limit FAO-derived ROS, with germ-cell-specific Cpt1b loss causing sheath defects and reduced motility [#3]. Through a KEAP1 interaction that sustains NRF2 [#16] and roles in cardiomyocyte hypertrophy and proliferation [#18, #19], CPT1B links lipid catabolism to redox homeostasis and cell fate.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established CPT1B as the muscle isoform catalyzing the rate-limiting step of long-chain FAO and showed that its splice variants are catalytically inactive, ruling out splicing as a mechanism for tuning malonyl-CoA inhibition.\",\n      \"evidence\": \"Heterologous expression of splice variants in Pichia pastoris with enzymatic activity assays and genomic/cDNA analysis\",\n      \"pmids\": [\"12015320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the physiological regulators of malonyl-CoA sensitivity\", \"No structural model of the active enzyme\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that exercise drives CPT1B transcription through MEF2A recruitment and HDAC5 derepression, linking physical activity to muscle FAO capacity.\",\n      \"evidence\": \"ChIP, Cpt1b promoter luciferase reporters, MEF2A/HDAC5 overexpression in C2C12 cells, and fractionation in mouse muscle\",\n      \"pmids\": [\"25213552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether MEF2A/HDAC5 control CPT1B in non-muscle tissues\", \"Upstream signals coupling exercise to HDAC5 phosphorylation only partially defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified epigenetic control of CPT1B by CpG methylation and transcription factor occupancy, providing a mechanism for blunted FAO gene induction in obesity.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, and transcription factor binding assays in primary human skeletal muscle cultures\",\n      \"pmids\": [\"26058865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between specific methylated sites and clinical phenotype is correlative\", \"Did not test methylation editing in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CPT1B-driven FAO is a source of cardiac ROS, since cardiac CPT1B silencing protected obese hearts from remodeling at the cost of lipid accumulation.\",\n      \"evidence\": \"Cardiac-specific lentiviral CPT1B knockdown in high-fat-diet mice with echocardiography, histology, and ROS measurement\",\n      \"pmids\": [\"27804274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparently opposite to later studies where CPT1B overexpression is cardioprotective — context dependence unresolved\", \"Did not define how FAO flux generates ROS\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proved that malonyl-CoA inhibition of CPT1B sets the cardiac FAO rate in vivo and that loss of inhibition is buffered by transcriptional compensation.\",\n      \"evidence\": \"CPT1B E3A malonyl-CoA-insensitive knock-in mouse with perfused-heart FAO, metabolomics, proteomics, and transcriptomics\",\n      \"pmids\": [\"29635338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the compensatory FAO gene downregulation not identified\", \"Long-term consequences for cardiac function not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an oxygen-sensitive post-translational switch in which PHD2/3 hydroxylate CPT1B at Pro295 to enable VDAC1 binding and LCFA oxidation.\",\n      \"evidence\": \"Co-IP, P295A mutagenesis with functional rescue, and PHD2/3-knockout cardiomyocytes with FAO assays\",\n      \"pmids\": [\"34610308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VDAC1 binding mechanistically supports FAO is unresolved\", \"Stoichiometry and dynamics of hydroxylation under physiological oxygen tension not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added EZH2/H3K27me3 repression of CPT1B as a node in cardiac hypertrophy, antagonized by lncRNA uc.323.\",\n      \"evidence\": \"ChIP, gain/loss-of-function in cardiomyocytes, CPT1B overexpression rescue, and aortic banding mice\",\n      \"pmids\": [\"31735087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How uc.323 directs EZH2 away from the CPT1B locus not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CPT1B downstream of myostatin signaling, with SMAD3 directly binding its promoter to restrain muscle FAO.\",\n      \"evidence\": \"ChIP for SMAD3 promoter binding, Mstn-knockdown mice, and CPT1 activity/fatty acid composition assays\",\n      \"pmids\": [\"36002433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMAD3 acts as direct repressor or via cofactors unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CPT1B to redox control via a KEAP1 interaction sustaining NRF2 and protecting cancer cells from ferroptosis, and identified divergent cancer transcriptional regulators (ZNF263 activating, MITF repressing).\",\n      \"evidence\": \"Co-IP, siRNA knockdown with ferroptosis assays and xenografts; dual-luciferase and ChIP in lung adenocarcinoma cells\",\n      \"pmids\": [\"38302326\", \"39500874\", \"38016436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KEAP1 binding depends on CPT1B catalytic activity unknown\", \"Reciprocal validation of KEAP1 interaction limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a non-metabolic structural and rheostat role in sperm, where TEX44 anchors mitochondria into the sheath and restrains CPT1B activity to limit FAO-derived ROS.\",\n      \"evidence\": \"Co-IP, purified-protein in vitro activity assays, Tex44 and germ-cell-specific Cpt1b knockout mice, and patient whole-exome sequencing\",\n      \"pmids\": [\"40849303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TEX44 binding biochemically inhibits CPT1B not resolved\", \"Whether the mitochondrial-glue role requires CPT1B enzymatic function unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified lysine-321 crotonylation, written by P300 and protected by CBP, as a disease-associated PTM that impairs CPT1B and drives endotoxic cardiomyopathy.\",\n      \"evidence\": \"Crotonylproteomics, K321R mutagenesis with rescue, IP-based writer identification, and AAV9 cardiac overexpression in rats\",\n      \"pmids\": [\"42209697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Eraser enzyme for K321cr not identified\", \"Crosstalk with Pro295 hydroxylation not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many transcriptional, epigenetic, and post-translational inputs are integrated to set CPT1B activity in a given tissue, and whether its enzymatic versus scaffolding/redox roles are separable, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking Pro295 hydroxylation, K321 crotonylation, and VDAC1/TEX44/KEAP1 binding\", \"Tissue-specific selection among the documented transcriptional regulators undefined\", \"Reconciliation of protective vs. ROS-generating roles of CPT1B-driven FAO across heart contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 14, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 7, 8, 9, 10, 14, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VDAC1\", \"PHD2\", \"PHD3\", \"TEX44\", \"KEAP1\", \"P300\", \"CBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}