{"gene":"SLC27A5","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2006,"finding":"FATP5 (SLC27A5) is exclusively expressed in liver and localizes to the basal plasma membrane of hepatocytes. Knockout of FATP5 significantly reduced long-chain fatty acid (LCFA) uptake by isolated hepatocytes, and overexpression increased 14C-oleate uptake in mammalian cells, establishing FATP5 as a required mediator of hepatocellular LCFA uptake.","method":"FATP5 knockout mouse model (hepatocyte isolation/uptake assays), overexpression with 14C-oleate uptake, immunolocalization","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with direct lipid uptake readout, subcellular localization by fractionation/imaging, replicated in vivo and in vitro in a single rigorous study","pmids":["16618416"],"is_preprint":false},{"year":2011,"finding":"Fatp5 knockdown in mice increased the proportion of unconjugated bile acids ~100-fold, confirming FATP5's enzymatic role in bile acid reconjugation in vivo. However, Fatp5 knockdown did not alleviate ApoB-siRNA-induced hepatic triglyceride accumulation, indicating FATP5-mediated fatty acid uptake is not the dominant pathway for this form of steatosis.","method":"siRNA/shRNA knockdown of Fatp5 in mice; bile acid profiling; hepatic triglyceride measurement","journal":"Lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with biochemical readout (bile acid profiling), single lab, two orthogonal endpoints","pmids":["21826528"],"is_preprint":false},{"year":2019,"finding":"SLC27A5 knockout in hepatoma cells increases polyunsaturated lipids, elevates NADP+/NADPH ratio, ROS, and lipid peroxidation, leading to 4-HNE accumulation. Mass spectrometry showed 4-HNE directly modifies cysteine residues Cys513 and Cys518 on KEAP1, activating the KEAP1/NRF2 pathway and upregulating NRF2 target genes including TXNRD1.","method":"SLC27A5 gain- and loss-of-function in HCC cells; mass spectrometry identification of 4-HNE-modified KEAP1 cysteines; NRF2/TXNRD1 expression assays; in vivo tumor models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct MS identification of PTM site on KEAP1 combined with reciprocal gain/loss-of-function and in vivo validation; multiple orthogonal methods in one study","pmids":["31367013"],"is_preprint":false},{"year":2021,"finding":"FATP5 knockdown in HCC cells promotes glycolytic flux and ATP production, suppressing AMPK activity and activating downstream mTOR signaling to support epithelial-mesenchymal transition, migration, and invasion. Metformin-mediated AMPK activation reversed EMT in FATP5-depleted cells, placing FATP5 upstream of the AMPK/mTOR axis.","method":"FATP5 knockdown/overexpression in HCC cells; glycolytic flux and ATP assays; AMPK/mTOR phosphorylation analysis; metformin rescue experiment; in vivo mouse models","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with biochemical pathway readout and pharmacological epistasis rescue, single lab","pmids":["34772914"],"is_preprint":false},{"year":2023,"finding":"SLC27A5 loss enhances glutathione reductase (GSR) expression in an NRF2-dependent manner, maintaining GSH homeostasis and suppressing ferroptosis, thereby conferring sorafenib resistance. Genetic or pharmacological GSR inhibition (BCNU/carmustine) depleted GSH and restored lipid peroxide accumulation, re-sensitizing SLC27A5-knockout HCC cells to sorafenib-induced ferroptosis.","method":"SLC27A5 knockout and knockdown in HCC cells; GSR expression and GSH measurement; ferroptosis assays; in vivo tumor growth with sorafenib + BCNU combination","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined biochemical mechanism (NRF2/GSR/GSH axis) and in vivo validation, single lab","pmids":["36635256"],"is_preprint":false},{"year":2023,"finding":"SLC27A5 deficiency results in accumulation of unconjugated bile acids—particularly cholic acid (CA)—in the liver. Accumulated CA activates hepatic stellate cells (HSCs) by upregulating EGR3 expression, driving liver fibrosis. AAV-mediated SLC27A5 re-expression or reduction of CA levels with ASBT inhibitor A4250 ameliorated fibrosis in Slc27a5-/- mice. RUNX2 was identified as a transcriptional repressor of SLC27A5.","method":"Slc27a5 knockout mice; CCl4/TAA-induced fibrosis models; bile acid profiling; HSC activation assays; AAV rescue; ASBT inhibitor treatment; RUNX2 ChIP/reporter assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with spontaneous phenotype, mechanistic pathway (CA→EGR3→HSC activation) demonstrated with multiple rescue approaches (AAV, pharmacological)","pmids":["37957540"],"is_preprint":false},{"year":2023,"finding":"SLC27A5 exerts a non-canonical function by interacting with IGF2BP3 to prevent its nuclear translocation, thereby inhibiting IGF2BP3 binding to target mRNA and modulating alternative splicing of PIP4K2A pre-mRNA. Loss of SLC27A5 elevates the PIP4K2A-S isoform, which enhances p85 stability and activates PI3K signaling to promote HCC metastasis.","method":"Co-immunoprecipitation; subcellular fractionation; alternative splicing analysis by RNA-seq; IGF2BP3 knockdown/overexpression; p85 stability assays; AAV-Slc27a5 rescue; RNA decoy oligonucleotides","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for protein interaction, RNA-seq for splicing, multiple rescue strategies, single lab","pmids":["38059827"],"is_preprint":false},{"year":2024,"finding":"UBAP2, through the ubiquitin-proteasome system, degrades SLC27A5, leading to decreased RAD51 expression (homologous recombination) and radioresistance in HCC. Ectopic SLC27A5 expression reversed the radioresistance conferred by UBAP2, establishing SLC27A5 as a substrate of UBAP2-mediated ubiquitin-proteasome degradation.","method":"UBAP2 knockdown/overexpression; SLC27A5 rescue experiments; ubiquitin-proteasome pathway assays; RAD51 and CTIP expression analysis; in vitro and in vivo radiation resistance assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (rescue experiment) combined with ubiquitin-proteasome mechanism, single lab","pmids":["39186963"],"is_preprint":false},{"year":2024,"finding":"FATP5 is the predominant mediator of fatty acid uptake required for intrahepatic cholangiocarcinoma (ICC) growth in vivo. Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5 both suppressed ICC tumor growth, and lipidomics confirmed dramatically elevated fatty acid levels in ICC.","method":"Fatp5 knockout mice; AAV-shRNA silencing; luciferase-based fatty acid uptake monitoring in vivo (FFA-Luc); lipidomics","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal in vivo loss-of-function approaches (genetic KO and AAV-shRNA) with direct functional readout of FA uptake and lipidomics","pmids":["38358323"],"is_preprint":false},{"year":2024,"finding":"SLC27A5 reduces expression of PABPC1, an alternative polyadenylation (APA)-associated factor, thereby promoting use of the proximal polyadenylation site of METTL14 mRNA. This produces the METTL14-US isoform, which escapes miRNA-mediated repression due to a shorter 3'UTR, increasing METTL14 protein and suppressing HCC cancer stem cell stemness.","method":"Immunoprecipitation-mass spectrometry; RNA-seq for APA events; SLC27A5 overexpression/knockdown; PABPC1 expression analysis; isoform-specific expression assays; stemness assays","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for interaction discovery combined with RNA-seq and functional stemness readout, single lab","pmids":["40290127"],"is_preprint":false},{"year":2025,"finding":"Hypoxia suppresses SLC27A5 transcription by repressing hepatocyte nuclear factor 4 alpha (HNF4A). Loss of SLC27A5 activates the AKT pathway, increases CDK2 and Cyclin E1 expression, and promotes G1-to-S phase transition in HCC cells. HNF4A activation by Benfluorex combined with AKT inhibitor MK2206 synergistically inhibited HCC xenograft growth.","method":"In vitro and in vivo hypoxia models; HNF4A knockdown/overexpression; SLC27A5 promoter reporter assays; cell cycle analysis; AKT pathway phosphorylation; xenograft model with pharmacological combination","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (hypoxia→HNF4A→SLC27A5→AKT→cell cycle) with multiple in vitro and in vivo validations, single lab","pmids":["39938688"],"is_preprint":false},{"year":2025,"finding":"FATP5 knockdown in MASH models reduces pro-ferroptotic PUFA-containing lipids, which alleviates suppression of SREBP1, subsequently upregulating its transcriptional target SCD1 (stearoyl-CoA desaturase 1). AAV-mediated SCD1 overexpression in vivo attenuated hepatic inflammation and liver injury in MASH by inhibiting ferroptosis, identifying a FATP5→PUFA-lipids→SREBP1/SCD1 axis.","method":"FATP5 knockdown in vitro and MCD diet-induced MASH mouse model; untargeted lipidomics; SREBP1/SCD1 expression analysis; ferroptosis inhibitor (ferrostatin-1) treatment; AAV-SCD1 in vivo overexpression","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with lipidomics and in vivo AAV rescue establishing mechanistic axis, single lab","pmids":["40840619"],"is_preprint":false},{"year":2026,"finding":"FATP5 is necessary for hepatic N-acyl taurine (NAT) synthesis, acting upstream of BAAT through its acyl-CoA synthetase activity to generate fatty acyl-CoA intermediates. In vivo knockdown of Slc27a5 confirmed that FATP5 is required for hepatic NAT synthesis, identifying a functional overlap between hepatic NAT and bile acid conjugation pathways.","method":"Liver transcriptomics in NAT hydrolase-deficient mice; in vivo siRNA/shRNA knockdown of Slc27a5; NAT and bile acid metabolite profiling","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with direct metabolite profiling demonstrating enzymatic role, single lab","pmids":["41780593"],"is_preprint":false},{"year":2026,"finding":"In HCC cells with impaired LCFA oxidation, SLC27A5 downregulation is driven by suppressed PPARα signaling (which represses SLC27A5 transcription). Loss of SLC27A5 reduces LCFA uptake, preventing lipotoxicity from unutilized LCFAs. HCC cells with low SLC27A5 compensate by relying on the glutamine reductive pathway for fatty acid biosynthesis, rendering them sensitive to glutaminase inhibition.","method":"SLC27A5 overexpression/knockdown in HCC cells; PPARα knockdown and agonist treatment; SLC27A5 promoter reporter assays; metabolic flux analysis (glutamine reductive pathway); glutaminase inhibitor sensitivity assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (PPARα→SLC27A5) with promoter reporter and metabolic flux analysis, single lab","pmids":["42202975"],"is_preprint":false},{"year":2026,"finding":"Sesaminol enhances PPARα occupancy on the Slc27a5 promoter, increasing SLC27A5-mediated fatty acid uptake and restoring mitochondrial β-oxidation flux, linking PPARα as a direct transcriptional activator of SLC27A5 in hepatic lipid metabolism.","method":"ChIP assay (PPARα on Slc27a5 promoter); transcriptomic analysis; in vitro HepG2 and in vivo HFD/alcohol mouse models; molecular docking","journal":"Molecular nutrition & food research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP experiment in a pharmacological context, single lab, no mutagenesis confirmation","pmids":["42170787"],"is_preprint":false}],"current_model":"SLC27A5/FATP5 is a liver-specific, basal plasma membrane-localized bifunctional enzyme that mediates hepatocellular long-chain fatty acid (LCFA) uptake and acts as a bile acid-CoA ligase required for bile acid reconjugation and N-acyl taurine synthesis; its transcription is activated by HNF4A and PPARα and repressed by RUNX2 and hypoxia; loss of SLC27A5 elevates polyunsaturated lipids and triggers 4-HNE modification of KEAP1 (at Cys513/518) to activate NRF2/TXNRD1 and NRF2/GSR antioxidant programs, shifts energy metabolism toward glycolysis to suppress AMPK and activate mTOR/EMT, accumulates unconjugated cholic acid to activate hepatic stellate cells via EGR3 driving fibrosis, and non-canonically sequesters IGF2BP3 in the cytoplasm to regulate alternative splicing of PIP4K2A and PABPC1-mediated alternative polyadenylation of METTL14, thereby suppressing PI3K signaling and cancer stem cell stemness; SLC27A5 protein stability is regulated by UBAP2-mediated ubiquitin-proteasome degradation, and its downregulation in HCC constitutes a survival adaptation to impaired LCFA oxidation that creates a therapeutic vulnerability to glutaminase inhibition."},"narrative":{"mechanistic_narrative":"SLC27A5 (FATP5) is a liver-specific, basal plasma membrane bifunctional protein that mediates hepatocellular long-chain fatty acid (LCFA) uptake and functions as a bile acid-CoA ligase required for bile acid reconjugation [PMID:16618416, PMID:21826528]. Its acyl-CoA synthetase activity also supplies fatty acyl-CoA intermediates upstream of BAAT for hepatic N-acyl taurine synthesis [PMID:41780593]. Transcription of SLC27A5 is activated by HNF4A and PPARα and repressed by RUNX2 and by hypoxia [PMID:37957540, PMID:39938688, PMID:42202975], while its protein level is controlled by UBAP2-mediated ubiquitin-proteasome degradation [PMID:39186963]. In hepatocellular carcinoma SLC27A5 acts as a tumor suppressor whose loss reshapes lipid and redox metabolism: depletion elevates polyunsaturated lipids and lipid peroxidation, generating 4-HNE that modifies KEAP1 at Cys513/Cys518 to activate NRF2 target genes including TXNRD1 and GSR, sustaining glutathione homeostasis and conferring ferroptosis and sorafenib resistance [PMID:31367013, PMID:36635256]. SLC27A5 loss also drives a glycolytic shift that suppresses AMPK and activates mTOR to promote epithelial-mesenchymal transition [PMID:34772914], and accumulated unconjugated cholic acid activates hepatic stellate cells via EGR3 to drive liver fibrosis [PMID:37957540]. Beyond metabolism, SLC27A5 sequesters IGF2BP3 in the cytoplasm to control PIP4K2A alternative splicing and PI3K signaling, and lowers PABPC1 to shift METTL14 alternative polyadenylation, together restraining metastasis and cancer stem cell stemness [PMID:38059827, PMID:40290127]. Reduced SLC27A5 in tumors with impaired LCFA oxidation represents a survival adaptation that redirects fatty acid biosynthesis toward the glutamine reductive pathway, creating a therapeutic vulnerability to glutaminase inhibition [PMID:42202975].","teleology":[{"year":2006,"claim":"Established that FATP5 is the required mediator of hepatocellular LCFA uptake, defining its core physiological function and tissue restriction.","evidence":"Knockout mouse and overexpression with 14C-oleate uptake plus immunolocalization to hepatocyte basal plasma membrane","pmids":["16618416"],"confidence":"High","gaps":["Did not resolve the catalytic mechanism coupling uptake to acyl-CoA synthesis","No structural model of the transporter/enzyme"]},{"year":2011,"claim":"Demonstrated FATP5's enzymatic role in bile acid reconjugation in vivo and bounded its contribution to hepatic steatosis.","evidence":"In vivo knockdown with bile acid profiling and hepatic triglyceride measurement","pmids":["21826528"],"confidence":"Medium","gaps":["Did not identify the bile acid-CoA ligase active site","Knockdown rather than full ablation"]},{"year":2019,"claim":"Showed that SLC27A5 loss links lipid peroxidation to redox signaling via a specific 4-HNE modification of KEAP1, explaining NRF2 activation in HCC.","evidence":"Reciprocal gain/loss-of-function in HCC cells with MS identification of 4-HNE-modified KEAP1 Cys513/518 and in vivo tumor models","pmids":["31367013"],"confidence":"High","gaps":["Did not establish whether NRF2 activation is sufficient for tumor suppression reversal","Other 4-HNE targets not excluded"]},{"year":2021,"claim":"Placed SLC27A5 upstream of the AMPK/mTOR axis, connecting its metabolic role to EMT and invasion.","evidence":"Knockdown/overexpression with glycolysis and ATP assays, AMPK/mTOR phosphorylation, and metformin rescue in vitro and in vivo","pmids":["34772914"],"confidence":"Medium","gaps":["Mechanism linking LCFA uptake loss to glycolytic flux not fully defined","Single lab"]},{"year":2023,"claim":"Defined the NRF2/GSR/GSH axis through which SLC27A5 loss suppresses ferroptosis and confers sorafenib resistance, and identified a re-sensitizing strategy.","evidence":"Knockout/knockdown HCC cells with GSH measurement, ferroptosis assays, and sorafenib+BCNU combination in vivo","pmids":["36635256"],"confidence":"Medium","gaps":["Clinical translatability of GSR inhibition untested","Single lab"]},{"year":2023,"claim":"Connected SLC27A5 deficiency to fibrosis via cholic acid accumulation activating stellate cells through EGR3, and identified RUNX2 as a transcriptional repressor.","evidence":"Knockout mouse fibrosis models, bile acid profiling, HSC activation assays, AAV and ASBT-inhibitor rescue, RUNX2 ChIP/reporter","pmids":["37957540"],"confidence":"High","gaps":["Direct EGR3 effector mechanism in HSCs not fully resolved","Human fibrosis correlation limited"]},{"year":2023,"claim":"Revealed a non-canonical RNA-regulatory function whereby SLC27A5 sequesters IGF2BP3 to control PIP4K2A splicing and PI3K signaling in metastasis.","evidence":"Reciprocal Co-IP, subcellular fractionation, RNA-seq splicing analysis, p85 stability assays, and AAV/RNA-decoy rescue","pmids":["38059827"],"confidence":"Medium","gaps":["How a metabolic enzyme binds IGF2BP3 structurally unknown","Single lab"]},{"year":2024,"claim":"Identified UBAP2 as an E3-pathway driver of SLC27A5 degradation linking its turnover to RAD51-mediated homologous recombination and radioresistance.","evidence":"UBAP2 knockdown/overexpression, SLC27A5 rescue, ubiquitin-proteasome assays, RAD51/CTIP expression, and in vivo radiation assays","pmids":["39186963"],"confidence":"Medium","gaps":["Specific ubiquitination sites on SLC27A5 not mapped","Direct vs indirect UBAP2 action not distinguished"]},{"year":2024,"claim":"Extended FATP5's fatty acid uptake role to a tumor-supporting function in intrahepatic cholangiocarcinoma growth.","evidence":"Knockout mice and AAV-shRNA silencing with in vivo FFA-Luc uptake monitoring and lipidomics","pmids":["38358323"],"confidence":"High","gaps":["Apparent context-dependent opposite roles (suppressor in HCC, pro-growth in ICC) not mechanistically reconciled"]},{"year":2024,"claim":"Showed SLC27A5 modulates METTL14 alternative polyadenylation via PABPC1 to suppress cancer stem cell stemness, broadening its RNA-regulatory reach.","evidence":"IP-MS, RNA-seq APA analysis, isoform-specific expression, and stemness assays with overexpression/knockdown","pmids":["40290127"],"confidence":"Medium","gaps":["Whether PABPC1 regulation is direct unclear","Single lab"]},{"year":2025,"claim":"Established that hypoxia represses SLC27A5 via HNF4A, with loss activating AKT and G1-to-S transition, and proposed a combination therapy.","evidence":"Hypoxia models, HNF4A knockdown/overexpression, promoter reporters, cell cycle analysis, and Benfluorex+MK2206 xenografts","pmids":["39938688"],"confidence":"Medium","gaps":["Mechanism linking SLC27A5 loss to AKT activation undefined","Single lab"]},{"year":2025,"claim":"Defined a FATP5→PUFA-lipid→SREBP1/SCD1 axis in MASH, showing knockdown is protective by relieving ferroptotic lipid pressure.","evidence":"Knockdown and MCD-diet MASH model, untargeted lipidomics, SREBP1/SCD1 analysis, ferrostatin-1, and AAV-SCD1 rescue","pmids":["40840619"],"confidence":"Medium","gaps":["Whether protective knockdown effect generalizes beyond MCD model unknown","Single lab"]},{"year":2026,"claim":"Assigned FATP5 an upstream role in hepatic N-acyl taurine synthesis through its acyl-CoA synthetase activity, overlapping with bile acid conjugation.","evidence":"Transcriptomics in NAT hydrolase-deficient mice and in vivo Slc27a5 knockdown with NAT and bile acid metabolite profiling","pmids":["41780593"],"confidence":"Medium","gaps":["Direct biochemical demonstration of acyl-CoA intermediate generation in vitro absent","Single lab"]},{"year":2026,"claim":"Showed PPARα represses SLC27A5 in HCC with impaired LCFA oxidation, with low SLC27A5 redirecting biosynthesis to the glutamine reductive pathway and creating glutaminase-inhibitor sensitivity.","evidence":"PPARα knockdown/agonist, promoter reporters, metabolic flux analysis, and glutaminase inhibitor sensitivity assays","pmids":["42202975"],"confidence":"Medium","gaps":["Apparent discrepancy with PPARα as activator elsewhere not reconciled","Single lab"]},{"year":null,"claim":"How SLC27A5 functions both as a tumor suppressor in HCC and a pro-growth fatty acid supplier in ICC, and how its enzymatic versus non-canonical RNA-regulatory activities are partitioned, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural basis for dual transporter/ligase and IGF2BP3-binding functions","Context-dependent transcriptional control by PPARα (activator vs repressor) unexplained","No human genetic disease link established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,12]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,5,6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["IGF2BP3","KEAP1","PABPC1","UBAP2","BAAT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2P5","full_name":"Long-chain fatty acid transport protein 5","aliases":["Bile acid-CoA ligase","BA-CoA ligase","BAL","Bile acyl-CoA synthetase","BACS","Cholate--CoA ligase","Fatty-acid-coenzyme A ligase, very long-chain 3","Long-chain-fatty-acid--CoA ligase","Solute carrier family 27 member 5","Very long-chain acyl-CoA synthetase homolog 2","VLCS-H2","VLCSH2","Very long-chain acyl-CoA synthetase-related protein","VLACS-related","VLACSR"],"length_aa":690,"mass_kda":75.4,"function":"May mediate the import of long-chain fatty acids (LCFA) by facilitating their transport across cell membranes (PubMed:20448275, PubMed:20530735). Also catalyzes the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates (PubMed:10479480). Mainly functions as a bile acyl-CoA synthetase catalyzing the activation of bile acids via ATP-dependent formation of bile acid CoA thioesters which is necessary for their subsequent conjugation with glycine or taurine (PubMed:10749848, PubMed:11980911). Both primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (deoxycholic acid and lithocholic acid) are the principal substrates (PubMed:10749848, PubMed:11980911). In vitro, activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate ((25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oate or THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol (PubMed:11980911). Plays an important role in hepatic fatty acid uptake and bile acid reconjugation and recycling but not in de novo synthesis of bile acids (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Microsome; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y2P5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC27A5","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC27A5","total_profiled":1310},"omim":[{"mim_id":"619232","title":"HYPERCHOLANEMIA, FAMILIAL 3; FHCA3","url":"https://www.omim.org/entry/619232"},{"mim_id":"604196","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 6; SLC27A6","url":"https://www.omim.org/entry/604196"},{"mim_id":"604194","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 4; SLC27A4","url":"https://www.omim.org/entry/604194"},{"mim_id":"604193","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 3; SLC27A3","url":"https://www.omim.org/entry/604193"},{"mim_id":"603314","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 5; SLC27A5","url":"https://www.omim.org/entry/603314"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":989.3}],"url":"https://www.proteinatlas.org/search/SLC27A5"},"hgnc":{"alias_symbol":["FATP5","VLACSR","VLCS-H2","VLCSH2","FACVL3","FLJ22987","ACSVL6","ACSB"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2P5","domains":[{"cath_id":"-","chopping":"4-80","consensus_level":"high","plddt":66.5603,"start":4,"end":80},{"cath_id":"3.40.50.980","chopping":"111-362","consensus_level":"medium","plddt":91.7505,"start":111,"end":362},{"cath_id":"2.30.38.10","chopping":"453-550","consensus_level":"high","plddt":89.9597,"start":453,"end":550},{"cath_id":"3.30.300.30","chopping":"555-686","consensus_level":"high","plddt":85.6436,"start":555,"end":686}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2P5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2P5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2P5-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC27A5","jax_strain_url":"https://www.jax.org/strain/search?query=SLC27A5"},"sequence":{"accession":"Q9Y2P5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2P5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2P5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2P5"}},"corpus_meta":[{"pmid":"16618416","id":"PMC_16618416","title":"Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16618416","citation_count":202,"is_preprint":false},{"pmid":"31367013","id":"PMC_31367013","title":"SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/31367013","citation_count":101,"is_preprint":false},{"pmid":"36635256","id":"PMC_36635256","title":"SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36635256","citation_count":81,"is_preprint":false},{"pmid":"32760200","id":"PMC_32760200","title":"Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32760200","citation_count":61,"is_preprint":false},{"pmid":"31602526","id":"PMC_31602526","title":"Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients.","date":"2019","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31602526","citation_count":48,"is_preprint":false},{"pmid":"35203444","id":"PMC_35203444","title":"Decreased SLC27A5 Suppresses Lipid Synthesis and Tyrosine Metabolism to Activate the Cell Cycle in Hepatocellular Carcinoma.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/35203444","citation_count":34,"is_preprint":false},{"pmid":"34772914","id":"PMC_34772914","title":"Fatty acid transport protein-5 (FATP5) deficiency enhances hepatocellular carcinoma progression and metastasis by reprogramming cellular energy metabolism and regulating the AMPK-mTOR signaling pathway.","date":"2021","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34772914","citation_count":31,"is_preprint":false},{"pmid":"21826528","id":"PMC_21826528","title":"ApoB siRNA-induced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5).","date":"2011","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/21826528","citation_count":31,"is_preprint":false},{"pmid":"37957540","id":"PMC_37957540","title":"Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37957540","citation_count":26,"is_preprint":false},{"pmid":"38059827","id":"PMC_38059827","title":"Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38059827","citation_count":15,"is_preprint":false},{"pmid":"38157255","id":"PMC_38157255","title":"Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38157255","citation_count":11,"is_preprint":false},{"pmid":"39186963","id":"PMC_39186963","title":"UBAP2 contributes to radioresistance by enhancing homologous recombination through SLC27A5 ubiquitination in hepatocellular carcinoma.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39186963","citation_count":8,"is_preprint":false},{"pmid":"38358323","id":"PMC_38358323","title":"FATP5 Is Indispensable for the Growth of Intrahepatic Cholangiocarcinoma.","date":"2024","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/38358323","citation_count":7,"is_preprint":false},{"pmid":"40840619","id":"PMC_40840619","title":"FATP5 deficiency alleviates MASH via remodeling hepatic lipid composition to suppress ferroptosis.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40840619","citation_count":5,"is_preprint":false},{"pmid":"39224804","id":"PMC_39224804","title":"FATP5 modulates biological activity and lipid metabolism in prostate cancer through the TEAD4-mediated Hippo signaling.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39224804","citation_count":4,"is_preprint":false},{"pmid":"39938688","id":"PMC_39938688","title":"Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A.","date":"2025","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39938688","citation_count":3,"is_preprint":false},{"pmid":"40290127","id":"PMC_40290127","title":"SLC27A5 inhibits cancer stem cells by inducing alternative polyadenylation of METTL14 in hepatocellular carcinoma.","date":"2024","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40290127","citation_count":2,"is_preprint":false},{"pmid":"40516455","id":"PMC_40516455","title":"In vivo protein half-life analysis identifies the SREBF1-SLC27a5 axis governs antioxidant response in preclinical alcoholic rat model.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/40516455","citation_count":0,"is_preprint":false},{"pmid":"42170787","id":"PMC_42170787","title":"Sesaminol Ameliorates Metabolic and Alcohol-Related Liver Injury by Activating the PPARα/Slc27a5 Axis-Driven Hepatic Fatty Acid β-Oxidation.","date":"2026","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/42170787","citation_count":0,"is_preprint":false},{"pmid":"41780593","id":"PMC_41780593","title":"The bile acid-CoA ligase, FATP5, is necessary for the synthesis of N-acyl taurines in the liver.","date":"2026","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/41780593","citation_count":0,"is_preprint":false},{"pmid":"42202975","id":"PMC_42202975","title":"SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/42202975","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13152,"output_tokens":4462,"usd":0.053193,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12584,"output_tokens":4479,"usd":0.087447,"stage2_stop_reason":"end_turn"},"total_usd":0.14064,"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\": 2006,\n      \"finding\": \"FATP5 (SLC27A5) is exclusively expressed in liver and localizes to the basal plasma membrane of hepatocytes. Knockout of FATP5 significantly reduced long-chain fatty acid (LCFA) uptake by isolated hepatocytes, and overexpression increased 14C-oleate uptake in mammalian cells, establishing FATP5 as a required mediator of hepatocellular LCFA uptake.\",\n      \"method\": \"FATP5 knockout mouse model (hepatocyte isolation/uptake assays), overexpression with 14C-oleate uptake, immunolocalization\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with direct lipid uptake readout, subcellular localization by fractionation/imaging, replicated in vivo and in vitro in a single rigorous study\",\n      \"pmids\": [\"16618416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fatp5 knockdown in mice increased the proportion of unconjugated bile acids ~100-fold, confirming FATP5's enzymatic role in bile acid reconjugation in vivo. However, Fatp5 knockdown did not alleviate ApoB-siRNA-induced hepatic triglyceride accumulation, indicating FATP5-mediated fatty acid uptake is not the dominant pathway for this form of steatosis.\",\n      \"method\": \"siRNA/shRNA knockdown of Fatp5 in mice; bile acid profiling; hepatic triglyceride measurement\",\n      \"journal\": \"Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with biochemical readout (bile acid profiling), single lab, two orthogonal endpoints\",\n      \"pmids\": [\"21826528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC27A5 knockout in hepatoma cells increases polyunsaturated lipids, elevates NADP+/NADPH ratio, ROS, and lipid peroxidation, leading to 4-HNE accumulation. Mass spectrometry showed 4-HNE directly modifies cysteine residues Cys513 and Cys518 on KEAP1, activating the KEAP1/NRF2 pathway and upregulating NRF2 target genes including TXNRD1.\",\n      \"method\": \"SLC27A5 gain- and loss-of-function in HCC cells; mass spectrometry identification of 4-HNE-modified KEAP1 cysteines; NRF2/TXNRD1 expression assays; in vivo tumor models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct MS identification of PTM site on KEAP1 combined with reciprocal gain/loss-of-function and in vivo validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"31367013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FATP5 knockdown in HCC cells promotes glycolytic flux and ATP production, suppressing AMPK activity and activating downstream mTOR signaling to support epithelial-mesenchymal transition, migration, and invasion. Metformin-mediated AMPK activation reversed EMT in FATP5-depleted cells, placing FATP5 upstream of the AMPK/mTOR axis.\",\n      \"method\": \"FATP5 knockdown/overexpression in HCC cells; glycolytic flux and ATP assays; AMPK/mTOR phosphorylation analysis; metformin rescue experiment; in vivo mouse models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with biochemical pathway readout and pharmacological epistasis rescue, single lab\",\n      \"pmids\": [\"34772914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC27A5 loss enhances glutathione reductase (GSR) expression in an NRF2-dependent manner, maintaining GSH homeostasis and suppressing ferroptosis, thereby conferring sorafenib resistance. Genetic or pharmacological GSR inhibition (BCNU/carmustine) depleted GSH and restored lipid peroxide accumulation, re-sensitizing SLC27A5-knockout HCC cells to sorafenib-induced ferroptosis.\",\n      \"method\": \"SLC27A5 knockout and knockdown in HCC cells; GSR expression and GSH measurement; ferroptosis assays; in vivo tumor growth with sorafenib + BCNU combination\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined biochemical mechanism (NRF2/GSR/GSH axis) and in vivo validation, single lab\",\n      \"pmids\": [\"36635256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC27A5 deficiency results in accumulation of unconjugated bile acids—particularly cholic acid (CA)—in the liver. Accumulated CA activates hepatic stellate cells (HSCs) by upregulating EGR3 expression, driving liver fibrosis. AAV-mediated SLC27A5 re-expression or reduction of CA levels with ASBT inhibitor A4250 ameliorated fibrosis in Slc27a5-/- mice. RUNX2 was identified as a transcriptional repressor of SLC27A5.\",\n      \"method\": \"Slc27a5 knockout mice; CCl4/TAA-induced fibrosis models; bile acid profiling; HSC activation assays; AAV rescue; ASBT inhibitor treatment; RUNX2 ChIP/reporter assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with spontaneous phenotype, mechanistic pathway (CA→EGR3→HSC activation) demonstrated with multiple rescue approaches (AAV, pharmacological)\",\n      \"pmids\": [\"37957540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC27A5 exerts a non-canonical function by interacting with IGF2BP3 to prevent its nuclear translocation, thereby inhibiting IGF2BP3 binding to target mRNA and modulating alternative splicing of PIP4K2A pre-mRNA. Loss of SLC27A5 elevates the PIP4K2A-S isoform, which enhances p85 stability and activates PI3K signaling to promote HCC metastasis.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation; alternative splicing analysis by RNA-seq; IGF2BP3 knockdown/overexpression; p85 stability assays; AAV-Slc27a5 rescue; RNA decoy oligonucleotides\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for protein interaction, RNA-seq for splicing, multiple rescue strategies, single lab\",\n      \"pmids\": [\"38059827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBAP2, through the ubiquitin-proteasome system, degrades SLC27A5, leading to decreased RAD51 expression (homologous recombination) and radioresistance in HCC. Ectopic SLC27A5 expression reversed the radioresistance conferred by UBAP2, establishing SLC27A5 as a substrate of UBAP2-mediated ubiquitin-proteasome degradation.\",\n      \"method\": \"UBAP2 knockdown/overexpression; SLC27A5 rescue experiments; ubiquitin-proteasome pathway assays; RAD51 and CTIP expression analysis; in vitro and in vivo radiation resistance assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (rescue experiment) combined with ubiquitin-proteasome mechanism, single lab\",\n      \"pmids\": [\"39186963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FATP5 is the predominant mediator of fatty acid uptake required for intrahepatic cholangiocarcinoma (ICC) growth in vivo. Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5 both suppressed ICC tumor growth, and lipidomics confirmed dramatically elevated fatty acid levels in ICC.\",\n      \"method\": \"Fatp5 knockout mice; AAV-shRNA silencing; luciferase-based fatty acid uptake monitoring in vivo (FFA-Luc); lipidomics\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal in vivo loss-of-function approaches (genetic KO and AAV-shRNA) with direct functional readout of FA uptake and lipidomics\",\n      \"pmids\": [\"38358323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC27A5 reduces expression of PABPC1, an alternative polyadenylation (APA)-associated factor, thereby promoting use of the proximal polyadenylation site of METTL14 mRNA. This produces the METTL14-US isoform, which escapes miRNA-mediated repression due to a shorter 3'UTR, increasing METTL14 protein and suppressing HCC cancer stem cell stemness.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry; RNA-seq for APA events; SLC27A5 overexpression/knockdown; PABPC1 expression analysis; isoform-specific expression assays; stemness assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for interaction discovery combined with RNA-seq and functional stemness readout, single lab\",\n      \"pmids\": [\"40290127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxia suppresses SLC27A5 transcription by repressing hepatocyte nuclear factor 4 alpha (HNF4A). Loss of SLC27A5 activates the AKT pathway, increases CDK2 and Cyclin E1 expression, and promotes G1-to-S phase transition in HCC cells. HNF4A activation by Benfluorex combined with AKT inhibitor MK2206 synergistically inhibited HCC xenograft growth.\",\n      \"method\": \"In vitro and in vivo hypoxia models; HNF4A knockdown/overexpression; SLC27A5 promoter reporter assays; cell cycle analysis; AKT pathway phosphorylation; xenograft model with pharmacological combination\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (hypoxia→HNF4A→SLC27A5→AKT→cell cycle) with multiple in vitro and in vivo validations, single lab\",\n      \"pmids\": [\"39938688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FATP5 knockdown in MASH models reduces pro-ferroptotic PUFA-containing lipids, which alleviates suppression of SREBP1, subsequently upregulating its transcriptional target SCD1 (stearoyl-CoA desaturase 1). AAV-mediated SCD1 overexpression in vivo attenuated hepatic inflammation and liver injury in MASH by inhibiting ferroptosis, identifying a FATP5→PUFA-lipids→SREBP1/SCD1 axis.\",\n      \"method\": \"FATP5 knockdown in vitro and MCD diet-induced MASH mouse model; untargeted lipidomics; SREBP1/SCD1 expression analysis; ferroptosis inhibitor (ferrostatin-1) treatment; AAV-SCD1 in vivo overexpression\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with lipidomics and in vivo AAV rescue establishing mechanistic axis, single lab\",\n      \"pmids\": [\"40840619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FATP5 is necessary for hepatic N-acyl taurine (NAT) synthesis, acting upstream of BAAT through its acyl-CoA synthetase activity to generate fatty acyl-CoA intermediates. In vivo knockdown of Slc27a5 confirmed that FATP5 is required for hepatic NAT synthesis, identifying a functional overlap between hepatic NAT and bile acid conjugation pathways.\",\n      \"method\": \"Liver transcriptomics in NAT hydrolase-deficient mice; in vivo siRNA/shRNA knockdown of Slc27a5; NAT and bile acid metabolite profiling\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with direct metabolite profiling demonstrating enzymatic role, single lab\",\n      \"pmids\": [\"41780593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In HCC cells with impaired LCFA oxidation, SLC27A5 downregulation is driven by suppressed PPARα signaling (which represses SLC27A5 transcription). Loss of SLC27A5 reduces LCFA uptake, preventing lipotoxicity from unutilized LCFAs. HCC cells with low SLC27A5 compensate by relying on the glutamine reductive pathway for fatty acid biosynthesis, rendering them sensitive to glutaminase inhibition.\",\n      \"method\": \"SLC27A5 overexpression/knockdown in HCC cells; PPARα knockdown and agonist treatment; SLC27A5 promoter reporter assays; metabolic flux analysis (glutamine reductive pathway); glutaminase inhibitor sensitivity assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (PPARα→SLC27A5) with promoter reporter and metabolic flux analysis, single lab\",\n      \"pmids\": [\"42202975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sesaminol enhances PPARα occupancy on the Slc27a5 promoter, increasing SLC27A5-mediated fatty acid uptake and restoring mitochondrial β-oxidation flux, linking PPARα as a direct transcriptional activator of SLC27A5 in hepatic lipid metabolism.\",\n      \"method\": \"ChIP assay (PPARα on Slc27a5 promoter); transcriptomic analysis; in vitro HepG2 and in vivo HFD/alcohol mouse models; molecular docking\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP experiment in a pharmacological context, single lab, no mutagenesis confirmation\",\n      \"pmids\": [\"42170787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC27A5/FATP5 is a liver-specific, basal plasma membrane-localized bifunctional enzyme that mediates hepatocellular long-chain fatty acid (LCFA) uptake and acts as a bile acid-CoA ligase required for bile acid reconjugation and N-acyl taurine synthesis; its transcription is activated by HNF4A and PPARα and repressed by RUNX2 and hypoxia; loss of SLC27A5 elevates polyunsaturated lipids and triggers 4-HNE modification of KEAP1 (at Cys513/518) to activate NRF2/TXNRD1 and NRF2/GSR antioxidant programs, shifts energy metabolism toward glycolysis to suppress AMPK and activate mTOR/EMT, accumulates unconjugated cholic acid to activate hepatic stellate cells via EGR3 driving fibrosis, and non-canonically sequesters IGF2BP3 in the cytoplasm to regulate alternative splicing of PIP4K2A and PABPC1-mediated alternative polyadenylation of METTL14, thereby suppressing PI3K signaling and cancer stem cell stemness; SLC27A5 protein stability is regulated by UBAP2-mediated ubiquitin-proteasome degradation, and its downregulation in HCC constitutes a survival adaptation to impaired LCFA oxidation that creates a therapeutic vulnerability to glutaminase inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC27A5 (FATP5) is a liver-specific, basal plasma membrane bifunctional protein that mediates hepatocellular long-chain fatty acid (LCFA) uptake and functions as a bile acid-CoA ligase required for bile acid reconjugation [#0, #1]. Its acyl-CoA synthetase activity also supplies fatty acyl-CoA intermediates upstream of BAAT for hepatic N-acyl taurine synthesis [#12]. Transcription of SLC27A5 is activated by HNF4A and PPARα and repressed by RUNX2 and by hypoxia [#5, #10, #13], while its protein level is controlled by UBAP2-mediated ubiquitin-proteasome degradation [#7]. In hepatocellular carcinoma SLC27A5 acts as a tumor suppressor whose loss reshapes lipid and redox metabolism: depletion elevates polyunsaturated lipids and lipid peroxidation, generating 4-HNE that modifies KEAP1 at Cys513/Cys518 to activate NRF2 target genes including TXNRD1 and GSR, sustaining glutathione homeostasis and conferring ferroptosis and sorafenib resistance [#2, #4]. SLC27A5 loss also drives a glycolytic shift that suppresses AMPK and activates mTOR to promote epithelial-mesenchymal transition [#3], and accumulated unconjugated cholic acid activates hepatic stellate cells via EGR3 to drive liver fibrosis [#5]. Beyond metabolism, SLC27A5 sequesters IGF2BP3 in the cytoplasm to control PIP4K2A alternative splicing and PI3K signaling, and lowers PABPC1 to shift METTL14 alternative polyadenylation, together restraining metastasis and cancer stem cell stemness [#6, #9]. Reduced SLC27A5 in tumors with impaired LCFA oxidation represents a survival adaptation that redirects fatty acid biosynthesis toward the glutamine reductive pathway, creating a therapeutic vulnerability to glutaminase inhibition [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that FATP5 is the required mediator of hepatocellular LCFA uptake, defining its core physiological function and tissue restriction.\",\n      \"evidence\": \"Knockout mouse and overexpression with 14C-oleate uptake plus immunolocalization to hepatocyte basal plasma membrane\",\n      \"pmids\": [\"16618416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the catalytic mechanism coupling uptake to acyl-CoA synthesis\", \"No structural model of the transporter/enzyme\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated FATP5's enzymatic role in bile acid reconjugation in vivo and bounded its contribution to hepatic steatosis.\",\n      \"evidence\": \"In vivo knockdown with bile acid profiling and hepatic triglyceride measurement\",\n      \"pmids\": [\"21826528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the bile acid-CoA ligase active site\", \"Knockdown rather than full ablation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that SLC27A5 loss links lipid peroxidation to redox signaling via a specific 4-HNE modification of KEAP1, explaining NRF2 activation in HCC.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function in HCC cells with MS identification of 4-HNE-modified KEAP1 Cys513/518 and in vivo tumor models\",\n      \"pmids\": [\"31367013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether NRF2 activation is sufficient for tumor suppression reversal\", \"Other 4-HNE targets not excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SLC27A5 upstream of the AMPK/mTOR axis, connecting its metabolic role to EMT and invasion.\",\n      \"evidence\": \"Knockdown/overexpression with glycolysis and ATP assays, AMPK/mTOR phosphorylation, and metformin rescue in vitro and in vivo\",\n      \"pmids\": [\"34772914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LCFA uptake loss to glycolytic flux not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the NRF2/GSR/GSH axis through which SLC27A5 loss suppresses ferroptosis and confers sorafenib resistance, and identified a re-sensitizing strategy.\",\n      \"evidence\": \"Knockout/knockdown HCC cells with GSH measurement, ferroptosis assays, and sorafenib+BCNU combination in vivo\",\n      \"pmids\": [\"36635256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical translatability of GSR inhibition untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SLC27A5 deficiency to fibrosis via cholic acid accumulation activating stellate cells through EGR3, and identified RUNX2 as a transcriptional repressor.\",\n      \"evidence\": \"Knockout mouse fibrosis models, bile acid profiling, HSC activation assays, AAV and ASBT-inhibitor rescue, RUNX2 ChIP/reporter\",\n      \"pmids\": [\"37957540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EGR3 effector mechanism in HSCs not fully resolved\", \"Human fibrosis correlation limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-canonical RNA-regulatory function whereby SLC27A5 sequesters IGF2BP3 to control PIP4K2A splicing and PI3K signaling in metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, RNA-seq splicing analysis, p85 stability assays, and AAV/RNA-decoy rescue\",\n      \"pmids\": [\"38059827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a metabolic enzyme binds IGF2BP3 structurally unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified UBAP2 as an E3-pathway driver of SLC27A5 degradation linking its turnover to RAD51-mediated homologous recombination and radioresistance.\",\n      \"evidence\": \"UBAP2 knockdown/overexpression, SLC27A5 rescue, ubiquitin-proteasome assays, RAD51/CTIP expression, and in vivo radiation assays\",\n      \"pmids\": [\"39186963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ubiquitination sites on SLC27A5 not mapped\", \"Direct vs indirect UBAP2 action not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FATP5's fatty acid uptake role to a tumor-supporting function in intrahepatic cholangiocarcinoma growth.\",\n      \"evidence\": \"Knockout mice and AAV-shRNA silencing with in vivo FFA-Luc uptake monitoring and lipidomics\",\n      \"pmids\": [\"38358323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent context-dependent opposite roles (suppressor in HCC, pro-growth in ICC) not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SLC27A5 modulates METTL14 alternative polyadenylation via PABPC1 to suppress cancer stem cell stemness, broadening its RNA-regulatory reach.\",\n      \"evidence\": \"IP-MS, RNA-seq APA analysis, isoform-specific expression, and stemness assays with overexpression/knockdown\",\n      \"pmids\": [\"40290127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PABPC1 regulation is direct unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that hypoxia represses SLC27A5 via HNF4A, with loss activating AKT and G1-to-S transition, and proposed a combination therapy.\",\n      \"evidence\": \"Hypoxia models, HNF4A knockdown/overexpression, promoter reporters, cell cycle analysis, and Benfluorex+MK2206 xenografts\",\n      \"pmids\": [\"39938688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SLC27A5 loss to AKT activation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a FATP5→PUFA-lipid→SREBP1/SCD1 axis in MASH, showing knockdown is protective by relieving ferroptotic lipid pressure.\",\n      \"evidence\": \"Knockdown and MCD-diet MASH model, untargeted lipidomics, SREBP1/SCD1 analysis, ferrostatin-1, and AAV-SCD1 rescue\",\n      \"pmids\": [\"40840619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protective knockdown effect generalizes beyond MCD model unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Assigned FATP5 an upstream role in hepatic N-acyl taurine synthesis through its acyl-CoA synthetase activity, overlapping with bile acid conjugation.\",\n      \"evidence\": \"Transcriptomics in NAT hydrolase-deficient mice and in vivo Slc27a5 knockdown with NAT and bile acid metabolite profiling\",\n      \"pmids\": [\"41780593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration of acyl-CoA intermediate generation in vitro absent\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed PPARα represses SLC27A5 in HCC with impaired LCFA oxidation, with low SLC27A5 redirecting biosynthesis to the glutamine reductive pathway and creating glutaminase-inhibitor sensitivity.\",\n      \"evidence\": \"PPARα knockdown/agonist, promoter reporters, metabolic flux analysis, and glutaminase inhibitor sensitivity assays\",\n      \"pmids\": [\"42202975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent discrepancy with PPARα as activator elsewhere not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC27A5 functions both as a tumor suppressor in HCC and a pro-growth fatty acid supplier in ICC, and how its enzymatic versus non-canonical RNA-regulatory activities are partitioned, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for dual transporter/ligase and IGF2BP3-binding functions\", \"Context-dependent transcriptional control by PPARα (activator vs repressor) unexplained\", \"No human genetic disease link established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IGF2BP3\", \"KEAP1\", \"PABPC1\", \"UBAP2\", \"BAAT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}