{"gene":"SLC25A20","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2004,"finding":"CACT (SLC25A20) transports acylcarnitines across the mitochondrial inner membrane in exchange for carnitine; the p.Arg133Trp substitution abolishes this transport activity, as demonstrated by expression of mutant protein in E. coli followed by functional reconstitution into liposomes.","method":"Site-directed mutagenesis, E. coli expression, functional reconstitution into liposomes (transport assay)","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with mutant protein, direct functional measurement of transport activity","pmids":["15365988"],"is_preprint":false},{"year":2021,"finding":"SLC25A20 (CAC) catalyzes electroneutral exchange of short, medium, and long-chain acyl-carnitines across the mitochondrial inner membrane for free carnitine; post-translational modifications (redox-sensitive) regulate its transport activity; site-directed mutagenesis combined with chemical targeting defined structure-function relationships including key residues involved in substrate binding and the transport mechanism.","method":"Site-directed mutagenesis, chemical modification, in vitro transport assay, bioinformatics/homology modeling","journal":"Biomolecules","confidence":"High","confidence_rationale":"Tier 1 / Strong — review synthesizing 30 years of reconstitution, mutagenesis, and kinetic data from multiple studies on the same protein","pmids":["33807231"],"is_preprint":false},{"year":2009,"finding":"Mouse CACT (SLC25A20) gene transcription is upregulated by PPARα and PPARδ (but not PPARγ) via a functional PPRE located in the 5'-UTR at position +45 to +57 relative to the transcription start site, as demonstrated by reporter assays and deletion/mutation analysis in liver cells.","method":"Reporter gene (luciferase) assay, deletion analysis, mutation analysis, PPARα-knockout mice, agonist treatment (WY-14,643, GW0742)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reporter assay with deletion/mutation analysis plus in vivo KO mouse confirmation, single lab but multiple orthogonal methods","pmids":["19577614"],"is_preprint":false},{"year":2009,"finding":"PPARα regulates human SLC25A20 expression via a peroxisome proliferator response element (PPRE) in the SLC25A20 promoter region, as demonstrated in human hepatoblastoma cells using a tetracycline-regulated PPARα expression system and luciferase reporter assays.","method":"Tetracycline-inducible PPARα overexpression, promoter-luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assay in single cell line, single lab","pmids":["19748481"],"is_preprint":false},{"year":2012,"finding":"Steroid Receptor Coactivator-3 (SRC-3) directly regulates CACT (SLC25A20) gene expression; SRC-3-knockout mice phenocopy human CACT deficiency (hypoketonemia, hypoglycemia, hyperammonemia, impaired neurologic/cardiac/skeletal muscle performance), and dietary short-chain fatty acid rescue reverses these phenotypes.","method":"SRC-3 genetic knockout mice, dietary rescue experiment, gene expression analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined metabolic phenotype, dietary rescue experiment, directly positions SRC-3 as transcriptional regulator of CACT","pmids":["22560224"],"is_preprint":false},{"year":2017,"finding":"SLC25A20 is a direct protein target of ingenol mebutate (IngMeb) and ingenol disoxate (IngDsx); these drugs inhibit SLC25A20 translocase activity in cells, leading to buildup of acylcarnitines and blockade of fatty acid oxidation (FAO), providing a mechanism for IngMeb-mediated mitochondrial dysfunction.","method":"Photoreactive clickable probe (chemical proteomics/photoaffinity labeling), quantitative proteomics, cellular acylcarnitine profiling, FAO assay","journal":"ACS central science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — chemical proteomics with photoaffinity probe plus functional validation (acylcarnitine accumulation, FAO blockade) in multiple cell types","pmids":["29296668"],"is_preprint":false},{"year":2022,"finding":"Pro/Gly residues of the PG-levels in SLC25A20 are critical for conformational changes during the transport cycle: P130A (H3), G268A (H6), and G220A (H5) mutations reduce CAC transport activity to <5% of wild type, while P30A (H1) and G121A (H3) mutations increase carnitine uptake to 217% and 112%, respectively. These residues guide substrate translocation by enabling tilting/kinking/bending of transmembrane helices.","method":"Alanine scanning site-directed mutagenesis, in vitro transport assay, 3D molecular modeling","journal":"International journal of biological macromolecules","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-based transport assay combined with mutagenesis and structural modeling, multiple residues systematically tested","pmids":["36122779"],"is_preprint":false},{"year":2023,"finding":"Mycotoxin patulin inhibits SLC25A20 (CAC) transport activity via covalent interaction with Cys136; site-directed mutagenesis of C136 abolishes patulin inhibition; the inhibition is competitive and occurs at or near the substrate-binding site, as confirmed by substrate protection experiments and mass spectrometry.","method":"Site-directed mutagenesis (C136 mutant), in vitro transport assay in proteoliposomes (native and recombinant protein), dose-response kinetics, substrate protection assay, mass spectrometry, molecular modeling","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis + reconstituted transport assay + mass spectrometry, multiple orthogonal methods in single study","pmids":["36768549"],"is_preprint":false},{"year":2024,"finding":"SLC25A20 forms transient dimers, as shown by Sarkosyl/PAGE and chemical cross-linking; comparative modeling based on ADP/ATP carrier dimeric crystal structures indicates dimerization does not alter the ping-pong transport mechanism.","method":"Sarkosyl/PAGE, chemical cross-linking reagents, comparative molecular modeling","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — biochemical cross-linking and native PAGE, single lab, no structural validation by crystallography or cryo-EM","pmids":["39334924"],"is_preprint":false},{"year":2023,"finding":"In silico analysis of SLC25A20 structural dynamics using homology modeling and molecular dynamics reveals asymmetric conformational changes in the cytosolic-to-matrix state transition; the pathogenic mutations Asp231His and Ala281Val alter the conformational dynamics of SLC25A20, providing a structural explanation for their loss of function in CACT deficiency.","method":"Homology modeling, molecular dynamics simulation, molecular docking","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational only, no experimental validation in this study","pmids":["36835358"],"is_preprint":false},{"year":2021,"finding":"Down-regulation of SLC25A20 in HCC cells (primarily due to upregulation of miR-132-3p) suppresses fatty acid oxidation and promotes tumor growth and metastasis via impaired G1-S cell cycle transition, induction of EMT, and reduced apoptosis; re-expression of SLC25A20 reverses these effects in vitro and in vivo.","method":"SLC25A20 knockdown/overexpression in HCC cell lines, in vivo xenograft, miR-132-3p manipulation, cell cycle, EMT marker, apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes and in vivo confirmation, pathway placement via FAO suppression; single lab","pmids":["33824298"],"is_preprint":false},{"year":2025,"finding":"SLC25A20 knockdown in pancreatic ductal adenocarcinoma cells reduces ATP production and inhibits cell growth via inactivation of mTOR signaling due to decreased ATP; in KPC/Slc25a20 mice, loss of SLC25A20 extends median survival by 3.1 weeks and reduces high-fat-diet-promoted tumor growth by 65-95%.","method":"SLC25A20 knockdown, proteome analysis, xenograft in HFD mice, KPC×KPC/Slc25a20 crossbreeding, ATP measurement, mTOR pathway analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro knockdown and in vivo genetic model with mechanistic pathway (ATP→mTOR), single lab but multiple orthogonal approaches","pmids":["40521210"],"is_preprint":false},{"year":2024,"finding":"The SLC25A20 variants c.476T>C and c.199-10T>G decrease protein stability of SLC25A20, reduce CPT1A and CPT2 mRNA expression, and cause SLC25A20 protein aggregation, thereby impairing the mitochondrial acylcarnitine/carnitine shuttle and inhibiting β-oxidation.","method":"Whole-exome sequencing, Western blot (protein stability/expression), quantitative PCR (CPT1A/CPT2 mRNA), immunofluorescence (subcellular localization/aggregation)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — in vitro functional studies with multiple methods but single lab, no direct transport assay","pmids":["39732347"],"is_preprint":false},{"year":2024,"finding":"EPA and DHA (n-3 PUFAs) upregulate CACT (SLC25A20) transcription in hepatic cells through a PPARα-independent mechanism involving GABP (GABPα/GABPβ) binding to two conserved GABP responsive elements within the -202 to -29 bp region of the CACT promoter; EPA/DHA induce nuclear accumulation of GABPα and enhance its binding to this region.","method":"Deletion promoter analysis, luciferase reporter assay, GABPα/β overexpression, ChIP assay, nuclear fractionation/immunoblot","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reporter assay with deletion analysis plus ChIP validation, multiple orthogonal methods, novel transcription factor identified","pmids":["39201781"],"is_preprint":false},{"year":2024,"finding":"Homozygous slc25a20 knockout zebrafish (generated by CRISPR/Cas9) display adipose tissue accumulation, cardiac hypertrophy with degenerated myocardial cells, hepatocyte lipid droplet vacuolation, and iron deposition in spleen and liver, recapitulating the pathological features of human CACT deficiency.","method":"CRISPR/Cas9 gene editing, histological examination, electron microscopy","journal":"Molecular genetics and metabolism reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO animal model with defined histopathological phenotype, single study, no biochemical transport assay","pmids":["39650084"],"is_preprint":false}],"current_model":"SLC25A20 (CACT/CAC) is a mitochondrial inner membrane transporter that catalyzes electroneutral exchange of acylcarnitines for free carnitine, enabling long-chain fatty acid β-oxidation; its transport activity depends on a single binding center-gated pore mechanism involving critical Pro/Gly residues in transmembrane helices and a Cys136 residue susceptible to inhibition; transcription is regulated by PPARα, PPARδ, and GABP via distinct promoter elements; SRC-3 acts as a coactivator of CACT expression; loss-of-function mutations cause CACT deficiency by reducing protein stability or abolishing transport, while pharmacological inhibition (by ingenol mebutate or patulin) blocks FAO; in cancer contexts, SLC25A20 suppresses tumor growth by sustaining FAO and ATP production through mTOR signaling."},"narrative":{"mechanistic_narrative":"SLC25A20 (CACT/CAC) is a mitochondrial inner membrane carrier that drives long-chain fatty acid β-oxidation by catalyzing the electroneutral exchange of short-, medium-, and long-chain acylcarnitines for free carnitine [PMID:15365988, PMID:33807231]. Transport proceeds through a single-pore, ping-pong mechanism in which conserved Pro/Gly residues across the transmembrane helices (notably P130, G220, G268) enable the helix tilting and bending that translocates substrate, while other PG residues (P30, G121) constrain it [PMID:36122779]; the protein assembles into transient dimers that do not alter this transport cycle [PMID:39334924]. Transport activity is redox-sensitive and gated near the substrate-binding center by Cys136, the residue covalently targeted by the inhibitor patulin and the site at which the pathogenic p.Arg133Trp substitution abolishes transport [PMID:15365988, PMID:33807231, PMID:36768549]; the drug ingenol mebutate likewise inhibits CACT, causing acylcarnitine accumulation and blockade of FAO [PMID:29296668]. Transcription is driven by PPARα and PPARδ through a 5'-UTR PPRE [PMID:19577614, PMID:19748481], by GABP through a PPARα-independent promoter element induced by n-3 PUFAs [PMID:39201781], and is coactivated by SRC-3, whose loss in mice phenocopies CACT deficiency and is rescued by short-chain fatty acid feeding [PMID:22560224]. Loss-of-function variants cause CACT deficiency by destabilizing or aggregating the protein and impairing the acylcarnitine/carnitine shuttle, recapitulated by zebrafish knockouts that develop adipose accumulation, cardiac hypertrophy, and hepatic lipid droplet vacuolation [PMID:39732347, PMID:39650084]. In cancer, SLC25A20 acts as a metabolic node coupling FAO to ATP production and mTOR signaling, with context-dependent roles in tumor growth [PMID:33824298, PMID:40521210].","teleology":[{"year":2004,"claim":"Established the core function of CACT as an acylcarnitine/carnitine antiporter and showed that a single disease residue is essential for transport, directly linking molecular activity to CACT deficiency.","evidence":"Site-directed mutagenesis with E. coli expression and reconstitution of wild-type and p.Arg133Trp protein into liposomes","pmids":["15365988"],"confidence":"High","gaps":["Did not resolve the full substrate range or the structural basis of the transport cycle","Mechanism of the R133W defect not structurally explained"]},{"year":2009,"claim":"Defined how CACT expression is transcriptionally coupled to fatty acid metabolism by identifying a functional PPRE responsive to PPARα and PPARδ.","evidence":"Luciferase reporter assays with deletion/mutation analysis, PPARα-knockout mice, and agonist treatment in liver cells (mouse); tetracycline-inducible PPARα reporter system (human)","pmids":["19577614","19748481"],"confidence":"High","gaps":["Did not address coactivator requirements","PPARδ contribution shown only in mouse"]},{"year":2012,"claim":"Identified SRC-3 as a transcriptional coactivator whose loss reproduces the metabolic syndrome of CACT deficiency, connecting CACT regulation to whole-organism FAO physiology.","evidence":"SRC-3 knockout mice with metabolic phenotyping and dietary short-chain fatty acid rescue","pmids":["22560224"],"confidence":"High","gaps":["Did not define the direct promoter element SRC-3 acts through","Relationship to PPAR-driven regulation not resolved"]},{"year":2017,"claim":"Revealed CACT as a pharmacological liability by showing ingenol mebutate directly inhibits its translocase activity, explaining drug-induced mitochondrial dysfunction.","evidence":"Photoaffinity chemical proteomics, quantitative proteomics, cellular acylcarnitine profiling and FAO assays across cell types","pmids":["29296668"],"confidence":"High","gaps":["Did not map the precise binding residue","In vitro reconstituted inhibition not tested"]},{"year":2021,"claim":"Consolidated the substrate breadth and redox-sensitive regulation of CACT and confirmed loss of SLC25A20 in hepatocellular carcinoma suppresses FAO and promotes tumor growth.","evidence":"Synthesis of reconstitution/mutagenesis/kinetic data (review); SLC25A20 knockdown/overexpression with miR-132-3p manipulation, xenografts, cell cycle/EMT/apoptosis assays in HCC","pmids":["33807231","33824298"],"confidence":"High","gaps":["Cancer mechanism beyond FAO suppression not detailed in HCC","Single lab for the HCC findings"]},{"year":2022,"claim":"Defined the structural mechanics of transport by pinpointing Pro/Gly residues whose mutation either abolishes or enhances carnitine uptake, establishing how helix flexibility drives substrate translocation.","evidence":"Alanine-scanning mutagenesis, reconstituted transport assays, and 3D molecular modeling","pmids":["36122779"],"confidence":"High","gaps":["No experimental high-resolution structure","Conformational states inferred from modeling, not captured directly"]},{"year":2023,"claim":"Identified Cys136 as a covalent inhibitory site near the substrate-binding center, mechanistically explaining patulin's competitive inhibition of CACT.","evidence":"C136 mutagenesis, reconstituted transport assays, substrate protection, mass spectrometry, and modeling","pmids":["36768549"],"confidence":"High","gaps":["Physiological/endogenous role of Cys136 redox modification not established","Structural model of the inhibited state unvalidated"]},{"year":2024,"claim":"Extended the disease and physiological model by linking specific variants to protein destabilization and aggregation, and by recapitulating CACT deficiency pathology in a vertebrate knockout.","evidence":"Whole-exome sequencing with Western blot, qPCR of CPT1A/CPT2, immunofluorescence; CRISPR/Cas9 slc25a20 knockout zebrafish with histology and electron microscopy","pmids":["39732347","39650084"],"confidence":"Medium","gaps":["Variant effects assessed without direct transport assay","Zebrafish phenotype not tied to biochemical transport deficit"]},{"year":2024,"claim":"Uncovered a PPARα-independent transcriptional route by showing n-3 PUFAs induce CACT via GABP binding to defined promoter elements, and showed CACT exists as a transient dimer that preserves the ping-pong cycle.","evidence":"Deletion promoter/luciferase assays, GABPα/β overexpression, ChIP, nuclear fractionation; Sarkosyl/PAGE and cross-linking with comparative modeling","pmids":["39201781","39334924"],"confidence":"High","gaps":["Dimerization shown biochemically without crystallography/cryo-EM","Interplay between GABP and PPARα regulation not resolved"]},{"year":2025,"claim":"Placed CACT as a metabolic dependency in pancreatic cancer by showing its loss lowers ATP, inactivates mTOR, and slows tumor growth in genetic and dietary models.","evidence":"SLC25A20 knockdown with proteomics, ATP and mTOR pathway analysis, HFD xenografts, and KPC/Slc25a20 mouse crossbreeding","pmids":["40521210"],"confidence":"Medium","gaps":["Apparent opposite cancer role versus HCC not reconciled","Single lab, mechanism downstream of mTOR not detailed"]},{"year":null,"claim":"How the multiple transcriptional inputs (PPARα/δ, SRC-3, GABP) are integrated, and how the same transporter exerts opposing growth effects across cancer types, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental high-resolution structure of human SLC25A20","Context-dependent tumor-suppressive vs. tumor-promoting roles not mechanistically reconciled","Endogenous regulators of Cys136 redox state unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43772","full_name":"Mitochondrial carnitine/acylcarnitine carrier protein","aliases":["Carnitine/acylcarnitine translocase","CAC","CACT","Solute carrier family 25 member 20"],"length_aa":301,"mass_kda":32.9,"function":"Mediates the electroneutral exchange of acylcarnitines (O-acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths (ranging from O-acetyl-(R)-carnitine to long-chain O-acyl-(R)-carnitines) with free carnitine ((R)-carnitine or L-carnitine) across the mitochondrial inner membrane, via a ping-pong mechanism (Probable) (PubMed:12892634, PubMed:18307102). Key player in the mitochondrial oxidation pathway, it translocates the fatty acids in the form of acylcarnitines into the mitochondrial matrix, where the carnitine palmitoyltransferase 2 (CPT-2) activates them to undergo fatty acid beta-oxidation (Probable). Catalyzes the unidirectional transport (uniport) of carnitine at lower rates than the antiport (exchange) (PubMed:18307102)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/O43772/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A20","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A20","total_profiled":1310},"omim":[{"mim_id":"615064","title":"SOLUTE CARRIER FAMILY 25 (CARNITINE/ACYLCARNITINE TRANSLOCASE),   MEMBER 29; SLC25A29","url":"https://www.omim.org/entry/615064"},{"mim_id":"614520","title":"ENCEPHALOMYOPATHY, MITOCHONDRIAL, DUE TO VOLTAGE-DEPENDENT ANION CHANNEL DEFICIENCY","url":"https://www.omim.org/entry/614520"},{"mim_id":"613698","title":"SOLUTE CARRIER FAMILY 25 (CARNITINE/ACYLCARNITINE TRANSLOCASE), MEMBER 20; SLC25A20","url":"https://www.omim.org/entry/613698"},{"mim_id":"607251","title":"TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 22; TIMM22","url":"https://www.omim.org/entry/607251"},{"mim_id":"212138","title":"CARNITINE-ACYLCARNITINE TRANSLOCASE DEFICIENCY; CACTD","url":"https://www.omim.org/entry/212138"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":138.7}],"url":"https://www.proteinatlas.org/search/SLC25A20"},"hgnc":{"alias_symbol":["CAC"],"prev_symbol":["CACT"]},"alphafold":{"accession":"O43772","domains":[{"cath_id":"1.50.40.10","chopping":"9-41_49-296","consensus_level":"high","plddt":89.5979,"start":9,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43772","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43772-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43772-F1-predicted_aligned_error_v6.png","plddt_mean":88.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A20","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A20"},"sequence":{"accession":"O43772","fasta_url":"https://rest.uniprot.org/uniprotkb/O43772.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43772/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43772"}},"corpus_meta":[{"pmid":"2558069","id":"PMC_2558069","title":"DNA fingerprinting with the oligonucleotide probe (CAC)5/(GTG)5: somatic stability and germline mutations.","date":"1989","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2558069","citation_count":87,"is_preprint":false},{"pmid":"32119646","id":"PMC_32119646","title":"Wu Mei Wan attenuates CAC by regulating gut microbiota and the NF-kB/IL6-STAT3 signaling pathway.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32119646","citation_count":58,"is_preprint":false},{"pmid":"15365988","id":"PMC_15365988","title":"Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15365988","citation_count":56,"is_preprint":false},{"pmid":"33807231","id":"PMC_33807231","title":"The Mitochondrial Carnitine Acyl-carnitine Carrier (SLC25A20): Molecular Mechanisms of Transport, Role in Redox Sensing and Interaction with Drugs.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33807231","citation_count":54,"is_preprint":false},{"pmid":"29296668","id":"PMC_29296668","title":"Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs.","date":"2017","source":"ACS central science","url":"https://pubmed.ncbi.nlm.nih.gov/29296668","citation_count":54,"is_preprint":false},{"pmid":"35590368","id":"PMC_35590368","title":"tRF-Val-CAC-016 modulates the transduction of CACNA1d-mediated MAPK signaling pathways to suppress the proliferation of gastric carcinoma.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35590368","citation_count":48,"is_preprint":false},{"pmid":"38443680","id":"PMC_38443680","title":"tiRNA-Val-CAC-2 interacts with FUBP1 to promote pancreatic cancer metastasis by activating c‑MYC 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Study protocol for the Hepatitis C: chain of addiction care (CAC) project.","date":"2022","source":"Addiction science & clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/36451175","citation_count":3,"is_preprint":false},{"pmid":"1680007","id":"PMC_1680007","title":"Individual-specific DNA fingerprinting in man using the oligonucleotide probe (GTG)5/(CAC)5.","date":"1991","source":"European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies","url":"https://pubmed.ncbi.nlm.nih.gov/1680007","citation_count":3,"is_preprint":false},{"pmid":"39201781","id":"PMC_39201781","title":"EPA and DHA Enhance CACT Promoter Activity by GABP/NRF2.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201781","citation_count":2,"is_preprint":false},{"pmid":"39650084","id":"PMC_39650084","title":"Homozygous slc25a20 zebrafish mutant reveals insights into carnitine-acylcarnitine translocase deficiency pathogenesis.","date":"2024","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/39650084","citation_count":2,"is_preprint":false},{"pmid":"36768549","id":"PMC_36768549","title":"The Mycotoxin Patulin Inhibits the Mitochondrial Carnitine/Acylcarnitine Carrier (SLC25A20) by Interaction with Cys136 Implications for Human Health.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768549","citation_count":2,"is_preprint":false},{"pmid":"39169309","id":"PMC_39169309","title":"The role of tRF-Val-CAC-010 in lung adenocarcinoma: implications for tumorigenesis and metastasis.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39169309","citation_count":2,"is_preprint":false},{"pmid":"38665026","id":"PMC_38665026","title":"Tropomyosin 2 Regulates Tumor Cell Proliferation, Immune Suppression, and Activation of the JNK Signaling Pathway in Colitis-Associated Cancer (CAC).","date":"2024","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38665026","citation_count":2,"is_preprint":false},{"pmid":"39571899","id":"PMC_39571899","title":"Exploring the mechanism of tiRNA-Val-CAC-002 in the pathogenesis of oral submucous fibrosis.","date":"2024","source":"Journal of oral biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39571899","citation_count":2,"is_preprint":false},{"pmid":"25402176","id":"PMC_25402176","title":"Hereditary and histologic characteristics of the CF1/b cac mouse cataract model.","date":"2014","source":"Comparative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25402176","citation_count":2,"is_preprint":false},{"pmid":"39792005","id":"PMC_39792005","title":"Ligilactobacillus salivarius LZZAY01 accelerated autophagy and apoptosis in colon cancer cells and improved gut microbiota in CAC mice.","date":"2025","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/39792005","citation_count":2,"is_preprint":false},{"pmid":"39267738","id":"PMC_39267738","title":"Genetically predicted HLA-DR+ natural killer cells as potential mediators in the lipid-coronary artery disease/ calcification (CAD/CAC) causal pathway.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39267738","citation_count":2,"is_preprint":false},{"pmid":"8582345","id":"PMC_8582345","title":"Oligonucleotide (CAC)5 fingerprinting: validity and reliability in paternity testing.","date":"1995","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/8582345","citation_count":2,"is_preprint":false},{"pmid":"31027119","id":"PMC_31027119","title":"Association of the MUTYH Gln324His (CAG/CAC) variant with cervical carcinoma and HR-HPV infection in a Chinese population.","date":"2019","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31027119","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50167,"output_tokens":3674,"usd":0.102805,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11498,"output_tokens":3451,"usd":0.071883,"stage2_stop_reason":"end_turn"},"total_usd":0.174688,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CACT (SLC25A20) transports acylcarnitines across the mitochondrial inner membrane in exchange for carnitine; the p.Arg133Trp substitution abolishes this transport activity, as demonstrated by expression of mutant protein in E. coli followed by functional reconstitution into liposomes.\",\n      \"method\": \"Site-directed mutagenesis, E. coli expression, functional reconstitution into liposomes (transport assay)\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with mutant protein, direct functional measurement of transport activity\",\n      \"pmids\": [\"15365988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLC25A20 (CAC) catalyzes electroneutral exchange of short, medium, and long-chain acyl-carnitines across the mitochondrial inner membrane for free carnitine; post-translational modifications (redox-sensitive) regulate its transport activity; site-directed mutagenesis combined with chemical targeting defined structure-function relationships including key residues involved in substrate binding and the transport mechanism.\",\n      \"method\": \"Site-directed mutagenesis, chemical modification, in vitro transport assay, bioinformatics/homology modeling\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — review synthesizing 30 years of reconstitution, mutagenesis, and kinetic data from multiple studies on the same protein\",\n      \"pmids\": [\"33807231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse CACT (SLC25A20) gene transcription is upregulated by PPARα and PPARδ (but not PPARγ) via a functional PPRE located in the 5'-UTR at position +45 to +57 relative to the transcription start site, as demonstrated by reporter assays and deletion/mutation analysis in liver cells.\",\n      \"method\": \"Reporter gene (luciferase) assay, deletion analysis, mutation analysis, PPARα-knockout mice, agonist treatment (WY-14,643, GW0742)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with deletion/mutation analysis plus in vivo KO mouse confirmation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19577614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PPARα regulates human SLC25A20 expression via a peroxisome proliferator response element (PPRE) in the SLC25A20 promoter region, as demonstrated in human hepatoblastoma cells using a tetracycline-regulated PPARα expression system and luciferase reporter assays.\",\n      \"method\": \"Tetracycline-inducible PPARα overexpression, promoter-luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assay in single cell line, single lab\",\n      \"pmids\": [\"19748481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Steroid Receptor Coactivator-3 (SRC-3) directly regulates CACT (SLC25A20) gene expression; SRC-3-knockout mice phenocopy human CACT deficiency (hypoketonemia, hypoglycemia, hyperammonemia, impaired neurologic/cardiac/skeletal muscle performance), and dietary short-chain fatty acid rescue reverses these phenotypes.\",\n      \"method\": \"SRC-3 genetic knockout mice, dietary rescue experiment, gene expression analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined metabolic phenotype, dietary rescue experiment, directly positions SRC-3 as transcriptional regulator of CACT\",\n      \"pmids\": [\"22560224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLC25A20 is a direct protein target of ingenol mebutate (IngMeb) and ingenol disoxate (IngDsx); these drugs inhibit SLC25A20 translocase activity in cells, leading to buildup of acylcarnitines and blockade of fatty acid oxidation (FAO), providing a mechanism for IngMeb-mediated mitochondrial dysfunction.\",\n      \"method\": \"Photoreactive clickable probe (chemical proteomics/photoaffinity labeling), quantitative proteomics, cellular acylcarnitine profiling, FAO assay\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — chemical proteomics with photoaffinity probe plus functional validation (acylcarnitine accumulation, FAO blockade) in multiple cell types\",\n      \"pmids\": [\"29296668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pro/Gly residues of the PG-levels in SLC25A20 are critical for conformational changes during the transport cycle: P130A (H3), G268A (H6), and G220A (H5) mutations reduce CAC transport activity to <5% of wild type, while P30A (H1) and G121A (H3) mutations increase carnitine uptake to 217% and 112%, respectively. These residues guide substrate translocation by enabling tilting/kinking/bending of transmembrane helices.\",\n      \"method\": \"Alanine scanning site-directed mutagenesis, in vitro transport assay, 3D molecular modeling\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-based transport assay combined with mutagenesis and structural modeling, multiple residues systematically tested\",\n      \"pmids\": [\"36122779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mycotoxin patulin inhibits SLC25A20 (CAC) transport activity via covalent interaction with Cys136; site-directed mutagenesis of C136 abolishes patulin inhibition; the inhibition is competitive and occurs at or near the substrate-binding site, as confirmed by substrate protection experiments and mass spectrometry.\",\n      \"method\": \"Site-directed mutagenesis (C136 mutant), in vitro transport assay in proteoliposomes (native and recombinant protein), dose-response kinetics, substrate protection assay, mass spectrometry, molecular modeling\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis + reconstituted transport assay + mass spectrometry, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36768549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC25A20 forms transient dimers, as shown by Sarkosyl/PAGE and chemical cross-linking; comparative modeling based on ADP/ATP carrier dimeric crystal structures indicates dimerization does not alter the ping-pong transport mechanism.\",\n      \"method\": \"Sarkosyl/PAGE, chemical cross-linking reagents, comparative molecular modeling\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — biochemical cross-linking and native PAGE, single lab, no structural validation by crystallography or cryo-EM\",\n      \"pmids\": [\"39334924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In silico analysis of SLC25A20 structural dynamics using homology modeling and molecular dynamics reveals asymmetric conformational changes in the cytosolic-to-matrix state transition; the pathogenic mutations Asp231His and Ala281Val alter the conformational dynamics of SLC25A20, providing a structural explanation for their loss of function in CACT deficiency.\",\n      \"method\": \"Homology modeling, molecular dynamics simulation, molecular docking\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational only, no experimental validation in this study\",\n      \"pmids\": [\"36835358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Down-regulation of SLC25A20 in HCC cells (primarily due to upregulation of miR-132-3p) suppresses fatty acid oxidation and promotes tumor growth and metastasis via impaired G1-S cell cycle transition, induction of EMT, and reduced apoptosis; re-expression of SLC25A20 reverses these effects in vitro and in vivo.\",\n      \"method\": \"SLC25A20 knockdown/overexpression in HCC cell lines, in vivo xenograft, miR-132-3p manipulation, cell cycle, EMT marker, apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes and in vivo confirmation, pathway placement via FAO suppression; single lab\",\n      \"pmids\": [\"33824298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A20 knockdown in pancreatic ductal adenocarcinoma cells reduces ATP production and inhibits cell growth via inactivation of mTOR signaling due to decreased ATP; in KPC/Slc25a20 mice, loss of SLC25A20 extends median survival by 3.1 weeks and reduces high-fat-diet-promoted tumor growth by 65-95%.\",\n      \"method\": \"SLC25A20 knockdown, proteome analysis, xenograft in HFD mice, KPC×KPC/Slc25a20 crossbreeding, ATP measurement, mTOR pathway analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro knockdown and in vivo genetic model with mechanistic pathway (ATP→mTOR), single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"40521210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SLC25A20 variants c.476T>C and c.199-10T>G decrease protein stability of SLC25A20, reduce CPT1A and CPT2 mRNA expression, and cause SLC25A20 protein aggregation, thereby impairing the mitochondrial acylcarnitine/carnitine shuttle and inhibiting β-oxidation.\",\n      \"method\": \"Whole-exome sequencing, Western blot (protein stability/expression), quantitative PCR (CPT1A/CPT2 mRNA), immunofluorescence (subcellular localization/aggregation)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — in vitro functional studies with multiple methods but single lab, no direct transport assay\",\n      \"pmids\": [\"39732347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EPA and DHA (n-3 PUFAs) upregulate CACT (SLC25A20) transcription in hepatic cells through a PPARα-independent mechanism involving GABP (GABPα/GABPβ) binding to two conserved GABP responsive elements within the -202 to -29 bp region of the CACT promoter; EPA/DHA induce nuclear accumulation of GABPα and enhance its binding to this region.\",\n      \"method\": \"Deletion promoter analysis, luciferase reporter assay, GABPα/β overexpression, ChIP assay, nuclear fractionation/immunoblot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reporter assay with deletion analysis plus ChIP validation, multiple orthogonal methods, novel transcription factor identified\",\n      \"pmids\": [\"39201781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Homozygous slc25a20 knockout zebrafish (generated by CRISPR/Cas9) display adipose tissue accumulation, cardiac hypertrophy with degenerated myocardial cells, hepatocyte lipid droplet vacuolation, and iron deposition in spleen and liver, recapitulating the pathological features of human CACT deficiency.\",\n      \"method\": \"CRISPR/Cas9 gene editing, histological examination, electron microscopy\",\n      \"journal\": \"Molecular genetics and metabolism reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO animal model with defined histopathological phenotype, single study, no biochemical transport assay\",\n      \"pmids\": [\"39650084\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A20 (CACT/CAC) is a mitochondrial inner membrane transporter that catalyzes electroneutral exchange of acylcarnitines for free carnitine, enabling long-chain fatty acid β-oxidation; its transport activity depends on a single binding center-gated pore mechanism involving critical Pro/Gly residues in transmembrane helices and a Cys136 residue susceptible to inhibition; transcription is regulated by PPARα, PPARδ, and GABP via distinct promoter elements; SRC-3 acts as a coactivator of CACT expression; loss-of-function mutations cause CACT deficiency by reducing protein stability or abolishing transport, while pharmacological inhibition (by ingenol mebutate or patulin) blocks FAO; in cancer contexts, SLC25A20 suppresses tumor growth by sustaining FAO and ATP production through mTOR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC25A20 (CACT/CAC) is a mitochondrial inner membrane carrier that drives long-chain fatty acid β-oxidation by catalyzing the electroneutral exchange of short-, medium-, and long-chain acylcarnitines for free carnitine [#0, #1]. Transport proceeds through a single-pore, ping-pong mechanism in which conserved Pro/Gly residues across the transmembrane helices (notably P130, G220, G268) enable the helix tilting and bending that translocates substrate, while other PG residues (P30, G121) constrain it [#6]; the protein assembles into transient dimers that do not alter this transport cycle [#8]. Transport activity is redox-sensitive and gated near the substrate-binding center by Cys136, the residue covalently targeted by the inhibitor patulin and the site at which the pathogenic p.Arg133Trp substitution abolishes transport [#0, #1, #7]; the drug ingenol mebutate likewise inhibits CACT, causing acylcarnitine accumulation and blockade of FAO [#5]. Transcription is driven by PPARα and PPARδ through a 5'-UTR PPRE [#2, #3], by GABP through a PPARα-independent promoter element induced by n-3 PUFAs [#13], and is coactivated by SRC-3, whose loss in mice phenocopies CACT deficiency and is rescued by short-chain fatty acid feeding [#4]. Loss-of-function variants cause CACT deficiency by destabilizing or aggregating the protein and impairing the acylcarnitine/carnitine shuttle, recapitulated by zebrafish knockouts that develop adipose accumulation, cardiac hypertrophy, and hepatic lipid droplet vacuolation [#12, #14]. In cancer, SLC25A20 acts as a metabolic node coupling FAO to ATP production and mTOR signaling, with context-dependent roles in tumor growth [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the core function of CACT as an acylcarnitine/carnitine antiporter and showed that a single disease residue is essential for transport, directly linking molecular activity to CACT deficiency.\",\n      \"evidence\": \"Site-directed mutagenesis with E. coli expression and reconstitution of wild-type and p.Arg133Trp protein into liposomes\",\n      \"pmids\": [\"15365988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full substrate range or the structural basis of the transport cycle\", \"Mechanism of the R133W defect not structurally explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined how CACT expression is transcriptionally coupled to fatty acid metabolism by identifying a functional PPRE responsive to PPARα and PPARδ.\",\n      \"evidence\": \"Luciferase reporter assays with deletion/mutation analysis, PPARα-knockout mice, and agonist treatment in liver cells (mouse); tetracycline-inducible PPARα reporter system (human)\",\n      \"pmids\": [\"19577614\", \"19748481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address coactivator requirements\", \"PPARδ contribution shown only in mouse\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified SRC-3 as a transcriptional coactivator whose loss reproduces the metabolic syndrome of CACT deficiency, connecting CACT regulation to whole-organism FAO physiology.\",\n      \"evidence\": \"SRC-3 knockout mice with metabolic phenotyping and dietary short-chain fatty acid rescue\",\n      \"pmids\": [\"22560224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the direct promoter element SRC-3 acts through\", \"Relationship to PPAR-driven regulation not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed CACT as a pharmacological liability by showing ingenol mebutate directly inhibits its translocase activity, explaining drug-induced mitochondrial dysfunction.\",\n      \"evidence\": \"Photoaffinity chemical proteomics, quantitative proteomics, cellular acylcarnitine profiling and FAO assays across cell types\",\n      \"pmids\": [\"29296668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the precise binding residue\", \"In vitro reconstituted inhibition not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the substrate breadth and redox-sensitive regulation of CACT and confirmed loss of SLC25A20 in hepatocellular carcinoma suppresses FAO and promotes tumor growth.\",\n      \"evidence\": \"Synthesis of reconstitution/mutagenesis/kinetic data (review); SLC25A20 knockdown/overexpression with miR-132-3p manipulation, xenografts, cell cycle/EMT/apoptosis assays in HCC\",\n      \"pmids\": [\"33807231\", \"33824298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cancer mechanism beyond FAO suppression not detailed in HCC\", \"Single lab for the HCC findings\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the structural mechanics of transport by pinpointing Pro/Gly residues whose mutation either abolishes or enhances carnitine uptake, establishing how helix flexibility drives substrate translocation.\",\n      \"evidence\": \"Alanine-scanning mutagenesis, reconstituted transport assays, and 3D molecular modeling\",\n      \"pmids\": [\"36122779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure\", \"Conformational states inferred from modeling, not captured directly\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified Cys136 as a covalent inhibitory site near the substrate-binding center, mechanistically explaining patulin's competitive inhibition of CACT.\",\n      \"evidence\": \"C136 mutagenesis, reconstituted transport assays, substrate protection, mass spectrometry, and modeling\",\n      \"pmids\": [\"36768549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological/endogenous role of Cys136 redox modification not established\", \"Structural model of the inhibited state unvalidated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the disease and physiological model by linking specific variants to protein destabilization and aggregation, and by recapitulating CACT deficiency pathology in a vertebrate knockout.\",\n      \"evidence\": \"Whole-exome sequencing with Western blot, qPCR of CPT1A/CPT2, immunofluorescence; CRISPR/Cas9 slc25a20 knockout zebrafish with histology and electron microscopy\",\n      \"pmids\": [\"39732347\", \"39650084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variant effects assessed without direct transport assay\", \"Zebrafish phenotype not tied to biochemical transport deficit\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a PPARα-independent transcriptional route by showing n-3 PUFAs induce CACT via GABP binding to defined promoter elements, and showed CACT exists as a transient dimer that preserves the ping-pong cycle.\",\n      \"evidence\": \"Deletion promoter/luciferase assays, GABPα/β overexpression, ChIP, nuclear fractionation; Sarkosyl/PAGE and cross-linking with comparative modeling\",\n      \"pmids\": [\"39201781\", \"39334924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dimerization shown biochemically without crystallography/cryo-EM\", \"Interplay between GABP and PPARα regulation not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed CACT as a metabolic dependency in pancreatic cancer by showing its loss lowers ATP, inactivates mTOR, and slows tumor growth in genetic and dietary models.\",\n      \"evidence\": \"SLC25A20 knockdown with proteomics, ATP and mTOR pathway analysis, HFD xenografts, and KPC/Slc25a20 mouse crossbreeding\",\n      \"pmids\": [\"40521210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposite cancer role versus HCC not reconciled\", \"Single lab, mechanism downstream of mTOR not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional inputs (PPARα/δ, SRC-3, GABP) are integrated, and how the same transporter exerts opposing growth effects across cancer types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental high-resolution structure of human SLC25A20\", \"Context-dependent tumor-suppressive vs. tumor-promoting roles not mechanistically reconciled\", \"Endogenous regulators of Cys136 redox state unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}