{"gene":"ACSL5","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":1998,"finding":"Rat ACS5 (ACSL5) is a long-chain acyl-CoA synthetase that activates a wide range of saturated fatty acids (C16–C18 range) with preference for C16–C18 unsaturated fatty acids; the purified recombinant enzyme produced in E. coli demonstrated this substrate specificity directly.","method":"Recombinant protein overproduction in E. coli, purification to near-homogeneity, in vitro enzymatic activity assay with fatty acid substrates","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified enzyme and substrate specificity profiling in a single rigorous study","pmids":["9722683"],"is_preprint":false},{"year":2007,"finding":"Oncostatin M (OM) transcriptionally activates ACSL5 (and ACSL3) in hepatic cells through the ERK signaling pathway, and overexpression of ACSL5 alone partitions fatty acids toward beta-oxidation rather than triglyceride synthesis; siRNA knockdown of ACSL5 abrogated the OM-induced enhancement of fatty acid oxidation.","method":"Transcriptional activation assay in HepG2 cells and hamster liver, siRNA knockdown, fatty acid oxidation assay, ACSL5 overexpression","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function (overexpression + siRNA knockdown) with functional oxidation readout in both cell and animal models","pmids":["17761945"],"is_preprint":false},{"year":2016,"finding":"ACSL5 knockout mice show ~80% reduction in ACSL activity in jejunal mucosa, reduced fat mass, increased energy expenditure, improved insulin sensitivity, elevated FGF21 (hepatic mRNA ~16-fold, serum ~13-fold), and delayed triglyceride absorption after olive oil gavage, establishing ACSL5 as a key regulator of intestinal fat absorption and whole-body energy metabolism.","method":"Whole-body ACSL5 knockout mouse model, ACSL enzyme activity assay, indirect calorimetry, olive oil gavage triglyceride absorption assay, insulin tolerance test, FGF21 measurement","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean whole-body KO with multiple orthogonal metabolic phenotypes and direct ACSL activity measurements","pmids":["26977393"],"is_preprint":false},{"year":2018,"finding":"The ACSL5 rs2419621 T allele is associated with higher levels of the 683-aa ACSL5 protein isoform (vs. the 739-aa isoform), which localizes predominantly to mitochondria and drives greater fatty acid oxidation; primary myotubes from T-allele carriers showed higher CO2 production from 14C-palmitic acid, and vastus lateralis biopsies showed higher mitochondrial complex I and II respiration.","method":"ACSL5 overexpression in C2C12 myoblasts, 14C-palmitic acid oxidation assay, subcellular localization by fractionation/Western blot, primary myotube respirometry, ex vivo mitochondrial high-resolution respirometry in human biopsies","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (14C oxidation, respirometry, localization), single lab, moderate sample sizes","pmids":["29605434"],"is_preprint":false},{"year":2016,"finding":"The genomic region harboring the T2D-associated SNP rs7903146 within TCF7L2 functions as a regulatory element that physically contacts the ACSL5 promoter; CRISPR-mediated deletion of this region reduces ACSL5 mRNA up to 30-fold and abolishes chromatin contacts with the ACSL5 promoter, identifying rs7903146 as a cis-regulatory variant controlling ACSL5 expression.","method":"CRISPR/Cas9 deletion in HCT116, global gene expression analysis, 4C and Capture-C chromatin conformation capture","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — CRISPR functional deletion combined with two independent chromatin conformation methods (4C + Capture C) in multiple cell lines and tissue validation","pmids":["27539148"],"is_preprint":false},{"year":2022,"finding":"Cytoplasmic SIRT6 deacetylates ACSL5 upon binding to saturated fatty acids (especially palmitic acid), which triggers SIRT6 nuclear export; deacetylation of ACSL5 by SIRT6 facilitates fatty acid oxidation and suppresses NAFLD. NASH tissues show reduced cytoplasmic SIRT6 and increased ACSL5 acetylation. Overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific KO mice.","method":"Co-IP, deacetylation assay (SIRT6-ACSL5 interaction), deacetylation-mimic overexpression in Sirt6 liver KO mice, fatty acid oxidation assay, hepatic ACSL5 OE and KD in vivo, patient/mouse NASH tissue analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical deacetylation assay, gain/loss-of-function in vivo, deacetylation-mimic rescue, replicated in patient tissue and mouse model","pmids":["36208627"],"is_preprint":false},{"year":2022,"finding":"Hepatic ACSL5 overexpression suppresses high-fat diet-induced NAFLD while ACSL5 depletion exacerbates it, demonstrating ACSL5 is a pro-fatty acid oxidation enzyme in liver whose activity is rate-limiting for NAFLD progression.","method":"Hepatic ACSL5 overexpression and shRNA knockdown in mice, HFD-induced NAFLD model, lipid accumulation and liver histology","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — paired gain- and loss-of-function in vivo with well-defined disease phenotype, same study as SIRT6 deacetylation findings","pmids":["36208627"],"is_preprint":false},{"year":2014,"finding":"ACSL5 overexpression in CaCo2 cells causes approximately 2-fold increase in mitochondrial mortalin (HSPA9), accompanied by disturbance of acyl-CoA/sphingolipid metabolism; this mitochondrial mortalin upregulation requires wild-type TP53 and is absent in cells with mutated TP53.","method":"Proteomics of isolated mitochondria from ACSL5 transfectants, tandem mass spectrometry lipid analysis, siRNA gene silencing, Western blotting, qRT-PCR in CaCo2, HEK293, Lovo, Colo320DM cells","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics, lipid MS, and siRNA in multiple cell lines, single lab","pmids":["24770931"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated silencing of ACSL5 in Jurkat T cells decreased PMA+Ionomycin-induced apoptosis to control levels and reduced mRNA expression of FAS, FASLG, and TNF, indicating ACSL5 promotes apoptosis in T lymphocytes.","method":"siRNA knockdown of ACSL5 in Jurkat T cells, flow cytometry apoptosis assay, qRT-PCR for apoptosis-related genes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean siRNA KD with functional apoptosis readout, single lab, single method for each endpoint","pmids":["22163040"],"is_preprint":false},{"year":2024,"finding":"USP29 interacts directly with ACSL5 and stabilizes it via K48-linked deubiquitination, preventing proteasomal degradation; the protective effect of USP29 on fatty acid beta-oxidation in MASLD is dependent on ACSL5.","method":"Co-IP, K48-linked ubiquitination assay, USP29 overexpression/deletion in mice and hepatocytes, ACSL5 rescue experiments, FAO gene expression","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by Co-IP, deubiquitination linkage characterized, ACSL5-dependence confirmed by rescue, single lab","pmids":["39355870"],"is_preprint":false},{"year":2024,"finding":"ACSL5 regulates MHC-I-mediated antigen presentation in tumor cells; elaidic acid (EA) is identified as a substrate/activator of ACSL5 that enhances MHC-I expression and sensitizes tumors to CD8+ T cell cytotoxicity and PD-1 blockade therapy.","method":"In vitro cytotoxicity assay with CD8+ T cells, in vivo tumor models, MHC-I expression analysis, ACSL5 substrate screening, ACSL5 overexpression/KD in tumor cells","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain/loss-of-function with defined immune readout and substrate identification, single lab, multiple methods","pmids":["38350448"],"is_preprint":false},{"year":2024,"finding":"Intestine-specific ACSL5 knockout (ACSL5IKO) mice are protected from diet-induced obesity exclusively through reduced food intake; this is mechanistically driven by increased FA content in the distal small intestine that elevates postprandial GLP-1 and PYY secretion; GLP-1 receptor antagonism partially restored food intake in ACSL5IKO mice.","method":"Intestine-specific conditional KO (tamoxifen-inducible villin-Cre), metabolic phenotyping, GLP-1/PYY measurement after TAG challenge, GLP-1 receptor antagonist treatment, dietary fat absorption and fecal lipid excreion assays","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with receptor antagonist epistasis experiment and multiple orthogonal readouts, mechanistic pathway established","pmids":["38499083"],"is_preprint":false},{"year":2024,"finding":"ACSL5 promotes lipoapoptosis in proximal tubular epithelial cells in diabetic kidney disease; ACSL5 knockdown reduces lipid deposition and lipoapoptosis while overexpression exacerbates them. STAT3 transcriptionally activates the ACSL5 promoter under high-glucose/palmitic acid conditions.","method":"ACSL5 KD and OE in BUMPT cells, Oil Red O staining, FFA ELISA, Western blot, STAT3 KD with ACSL5 OE rescue, ACSL5 promoter activity assay, HFD/STZ mouse model","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function in vitro and in vivo, promoter activity validation, single lab","pmids":["39557186"],"is_preprint":false},{"year":2025,"finding":"OTUB1 deubiquitinase interacts with ACSL5 and promotes its deubiquitination and protein stability, thereby enhancing fatty acid oxidation in APAP-induced acute liver injury; the protective effect of OTUB1 overexpression on FAO requires ACSL5.","method":"Mass spectrometry identification of ACSL5 as OTUB1 substrate, Co-IP, ubiquitination assay, OTUB1 OE/KD in vivo and in vitro, FAO measurement","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification, Co-IP, functional rescue, single lab","pmids":["40280245"],"is_preprint":false},{"year":2025,"finding":"AURKB inhibition suppresses RMS cell growth by inducing apoptosis and ferroptosis through a NPM1/SP1/ACSL5 signaling axis; ACSL5 is downstream of NPM1 and SP1 in mediating ferroptosis and apoptosis resistance in rhabdomyosarcoma cells.","method":"AURKB inhibition in vitro and in vivo, epistasis analysis with NPM1/SP1/ACSL5 knockdown/overexpression, apoptosis and ferroptosis assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established with gain/loss-of-function and defined pathway, single lab","pmids":["39927464"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer cells under glutamine deprivation, ACSL5 is upregulated by p53 transcriptionally and in turn competes with MIB1 to stabilize MDM2, suppressing p53 in a feedback loop; ACSL5 mitochondrial localization activates IDH2 to accelerate the TCA cycle, while also relieving p53-mediated inhibition of PGAM1 to drive glycolysis; these metabolic changes generate ROS and sensitize cells to oxaliplatin.","method":"ACSL5 OE/KD in colorectal cancer cells, p53 ChIP and transcriptional assay, MDM2 stabilization assay, PGAM1 functional assay, IDH2 activity assay, ROS measurement, oxaliplatin sensitivity assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays in single lab, pathway placement by epistasis, single study","pmids":["41355704"],"is_preprint":false},{"year":2025,"finding":"ACSL5 promotes fatty acid oxidation in bladder cancer cells; by enhancing FAO, ACSL5 increases intracellular acetyl-CoA levels, which in turn acetylate 53BP1 at K1360, enhancing recruitment of the p53-p21 senescence signaling axis in the nucleus and driving cellular senescence. ACSL5 expression is silenced in bladder cancer by DNMT1-mediated CpG island methylation.","method":"ACSL5 OE/KD, acetyl-CoA measurement, 53BP1 acetylation assay (K1360), p53-p21 pathway analysis, DNMT1 knockdown, in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mechanistic linkage between ACSL5 activity, acetyl-CoA production, and 53BP1 acetylation; single lab with multiple orthogonal methods","pmids":["40595416"],"is_preprint":false},{"year":2025,"finding":"IRF-1 signaling (downstream of interferon-gamma) induces ACSL5 expression in kidney tubular cells; ACSL5 maintains ATP production and cell viability and shapes the lipid composition of tubular cells by reducing ceramide accumulation and glycerolipid content.","method":"Transcriptomic, metabolomic, and lipidomic analysis of experimental models and patient cohorts, IRF-1 signaling perturbation, ACSL5 functional assays in kidney tubular cells","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with functional validation in cellular models, single lab, corroborated in patient data","pmids":["40546938"],"is_preprint":false},{"year":2025,"finding":"In breast cancer, JAB1 forms a transcriptional repressor complex with CRL4B (Cullin 4B-Ring E3 ligase) that co-occupies the promoters of PPARG and ACSL5, leading to their transcriptional repression and consequent activation of fatty acid metabolism.","method":"ChIP showing JAB1/CRL4B co-occupancy of ACSL5 promoter, CUL4B stabilization assay, gene expression analysis, proliferation/invasion assays with JAB1 manipulation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional promoter repression established, single lab","pmids":["41388188"],"is_preprint":false},{"year":2020,"finding":"ONECUT2 (OC2) transcription factor directly activates ACSL5 expression in gastric cancer cells; ChIP-seq and RNA-seq analyses revealed OC2 binding to the ACSL5 locus, and stable OC2 transfection increased ACSL5 expression.","method":"Stable OC2 transfection in GC cells, ChIP-seq, RNA-seq, OC2 knockdown with shRNA, correlation of OC2 and ACSL5 mRNA levels in patient database","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq in gain/loss-of-function system, single lab","pmids":["32129880"],"is_preprint":false},{"year":2016,"finding":"A splice variant of ACSL5 lacking exon 20 (ACSL5-Δ20) is causally linked to the migraine-associated SNP rs12355831; the functional variant rs2256368-G directly causes ~20–40% exon 20 skipping of ACSL5 mRNA, as shown by exon-skipping assay, implicating altered ACSL5 enzymatic activity (long-chain fatty acid activation) in mitochondria in migraine pathology.","method":"Exon-skipping assay, eQTL analysis in lymphoblastoid cell lines using GEUVADIS/1000 Genomes data","journal":"European journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — exon-skipping assay is direct, but functional consequence of the splice variant on ACSL5 enzyme activity was not measured; single lab","pmids":["27189022"],"is_preprint":false},{"year":2023,"finding":"ACSL5 knockdown reversed the anti-tumor effects of palmitic acid (C16:0) in A549 lung cancer cells (increased proliferation, apoptosis resistance, migration, invasion), and C16:0 treatment upregulated ACSL5 expression while inhibiting phosphorylated ERK, placing ACSL5 downstream of palmitic acid signaling in the ERK pathway.","method":"ACSL5 siRNA knockdown in A549 cells, C16:0 treatment, CCK-8, annexin V/PI apoptosis assay, wound healing/transwell assay, Western blot for pERK, mouse xenograft model","journal":"European journal of histochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth, pathway placement inferred from expression changes without direct enzymatic assay","pmids":["37946526"],"is_preprint":false},{"year":2026,"finding":"In lung-preferential metastatic breast cancer cells, ACSL5 mediates adaptation to the palmitic acid-enriched lung microenvironment by inducing COX2-mediated PGE2 accumulation, which activates PI3K/AKT and ERK signaling via EP4, promoting cancer cell survival and lung metastasis; ACSL5 also upregulates palmitoyltransferases to further enhance COX2 expression.","method":"ACSL5 gain/loss-of-function in breast cancer cell lines and mouse models, PGE2 measurement, signaling pathway analysis (PI3K/AKT, ERK), palmitoylation inhibitor (2-bromopalmitate) treatment, in vivo metastasis models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain/loss-of-function with defined mechanistic pathway in vitro and in vivo, single lab","pmids":["41570334"],"is_preprint":false},{"year":2025,"finding":"SR-CR herbal components enhance ACSL5 activity via SIRT6-mediated deacetylation, promoting fatty acid oxidation; validated by surface plasmon resonance and molecular docking confirming constituent-protein interactions.","method":"Western blot, immunofluorescence, surface plasmon resonance, molecular docking, in vivo HFD rat model, HepG2 cell model","journal":"Journal of ethnopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — surface plasmon resonance and molecular docking for ligand binding, but direct ACSL5 deacetylation and enzymatic activity not separately measured; single lab","pmids":["40254111"],"is_preprint":false}],"current_model":"ACSL5 is a mitochondria-associated long-chain acyl-CoA synthetase that activates long-chain fatty acids (preferring C16–C18 saturated and unsaturated species) to acyl-CoA thioesters, thereby directing fatty acids into beta-oxidation; its activity is positively regulated by SIRT6-mediated deacetylation and stabilized by USP29 and OTUB1 deubiquitination, while it is transcriptionally activated by oncostatin M (via ERK), IRF-1/interferon-gamma, p53, STAT3, and ONECUT2, and repressed by JAB1/CRL4B; in the intestine, ACSL5 controls long-chain fatty acid absorption and enteroendocrine (GLP-1/PYY) signaling; and in various tissues it modulates downstream processes including apoptosis, ferroptosis, cellular senescence (via acetyl-CoA-dependent 53BP1 acetylation), MHC-I antigen presentation, and tumor immunity."},"narrative":{"mechanistic_narrative":"ACSL5 is a long-chain acyl-CoA synthetase that activates C16–C18 fatty acids—with a preference for unsaturated species—to acyl-CoA thioesters, channeling fatty acids toward beta-oxidation rather than triglyceride synthesis [PMID:9722683, PMID:17761945]. Localizing predominantly to mitochondria, its activity is rate-limiting for hepatic fatty acid oxidation: overexpression suppresses diet-induced fatty liver while depletion exacerbates it [PMID:29605434, PMID:36208627]. In the intestine ACSL5 governs long-chain fatty acid absorption and whole-body energy balance, and its loss limits food intake by raising distal intestinal fatty acid content and potentiating GLP-1/PYY secretion [PMID:26977393, PMID:38499083]. ACSL5 protein levels and activity are tuned post-translationally—stabilized by USP29- and OTUB1-mediated deubiquitination [PMID:39355870, PMID:40280245] and activated by SIRT6-dependent deacetylation that licenses fatty acid oxidation and protects against fatty liver disease [PMID:36208627]—and its transcription is driven by oncostatin M via ERK, IRF-1/interferon-gamma, STAT3, p53, and ONECUT2, while being repressed by a JAB1/CRL4B complex [PMID:17761945, PMID:40546938, PMID:39557186, PMID:41355704, PMID:32129880, PMID:41388188]. Through its control of fatty acid flux ACSL5 acts as a metabolic node in disease contexts, promoting apoptosis and lipoapoptosis [PMID:22163040, PMID:39557186], shaping ferroptosis sensitivity downstream of NPM1/SP1 [PMID:39927464], enhancing MHC-I antigen presentation and tumor immunity [PMID:38350448], and driving acetyl-CoA-dependent 53BP1 acetylation that engages p53-p21 senescence signaling [PMID:40595416]. Regulatory variation at the ACSL5 locus, including a TCF7L2-region cis-regulatory element and the rs2419621 isoform-determining allele, links ACSL5 expression to fatty acid oxidation phenotypes and metabolic traits [PMID:27539148, PMID:29605434].","teleology":[{"year":1998,"claim":"Established the core biochemical identity of ACSL5 as a long-chain acyl-CoA synthetase and defined its substrate preference, answering what reaction the enzyme catalyzes.","evidence":"Recombinant rat enzyme purified from E. coli and assayed in vitro against fatty acid substrates","pmids":["9722683"],"confidence":"High","gaps":["Substrate profiling done with rat ortholog in vitro; tissue-specific substrate selectivity not addressed","No structural basis for chain-length preference"]},{"year":2007,"claim":"Showed ACSL5 directs fatty acids into beta-oxidation rather than triglyceride synthesis and is transcriptionally induced by oncostatin M through ERK, connecting enzyme activity to a metabolic fate decision.","evidence":"Transcriptional activation, siRNA knockdown, overexpression and fatty acid oxidation assays in HepG2 cells and hamster liver","pmids":["17761945"],"confidence":"High","gaps":["Direct ERK target on the ACSL5 promoter not mapped","Did not establish in vivo physiological consequence"]},{"year":2016,"claim":"Defined the in vivo physiological role of ACSL5 in intestinal fat absorption and whole-body energy metabolism, moving beyond cell-based oxidation readouts.","evidence":"Whole-body ACSL5 knockout mice with calorimetry, triglyceride absorption, insulin tolerance, and FGF21 measurements","pmids":["26977393"],"confidence":"High","gaps":["Whole-body KO cannot resolve tissue-of-origin for each phenotype","Mechanism linking ACSL5 loss to FGF21 elevation unresolved"]},{"year":2016,"claim":"Identified genomic regulation of ACSL5 expression, showing a TCF7L2-region T2D-associated variant acts as a cis-regulatory element physically contacting the ACSL5 promoter.","evidence":"CRISPR deletion in HCT116 plus 4C and Capture-C chromatin conformation capture","pmids":["27539148"],"confidence":"High","gaps":["Functional metabolic consequence of altered ACSL5 expression via this element not measured","Relationship to TCF7L2 protein function not separated"]},{"year":2018,"claim":"Linked an ACSL5 coding/isoform variant to mitochondrial localization and fatty acid oxidation capacity in human tissue, connecting genotype to functional respirometry.","evidence":"Isoform overexpression in myoblasts, 14C-palmitate oxidation, subcellular fractionation, and human biopsy respirometry","pmids":["29605434"],"confidence":"Medium","gaps":["Single lab, moderate sample size","Mechanism by which the 683-aa isoform localizes preferentially to mitochondria not defined"]},{"year":2022,"claim":"Revealed post-translational activation of ACSL5 by SIRT6-mediated deacetylation as a saturated-fatty-acid-responsive switch controlling fatty acid oxidation and fatty liver disease.","evidence":"Co-IP, deacetylation assay, deacetylation-mimic rescue in Sirt6 liver-KO mice, and NASH patient/mouse tissue analysis","pmids":["36208627"],"confidence":"High","gaps":["Acetylation site(s) on ACSL5 and their effect on catalysis not fully mapped","Coordination with deubiquitination control unknown"]},{"year":2024,"claim":"Established deubiquitination as a second post-translational control point, with USP29 stabilizing ACSL5 against proteasomal degradation to sustain hepatic fatty acid oxidation.","evidence":"Co-IP, K48-linked ubiquitination assay, USP29 gain/loss in mice and hepatocytes with ACSL5 rescue","pmids":["39355870"],"confidence":"Medium","gaps":["E3 ligase opposing USP29 not identified","Single lab"]},{"year":2024,"claim":"Defined the cellular mechanism of ACSL5-dependent appetite control, showing intestinal ACSL5 loss limits food intake via distal fatty acid–driven GLP-1/PYY secretion.","evidence":"Intestine-specific inducible KO with GLP-1/PYY measurement and GLP-1 receptor antagonist epistasis","pmids":["38499083"],"confidence":"High","gaps":["Sensing mechanism translating luminal fatty acids into enteroendocrine secretion not detailed","Contribution of PYY versus GLP-1 not fully separated"]},{"year":2024,"claim":"Connected ACSL5 fatty acid metabolism to tumor immunity by showing it regulates MHC-I antigen presentation and CD8+ T cell sensitivity, with elaidic acid as an activating substrate.","evidence":"CD8+ T cell cytotoxicity, in vivo tumor models, MHC-I analysis, and ACSL5 substrate screening with gain/loss-of-function","pmids":["38350448"],"confidence":"Medium","gaps":["Molecular link between acyl-CoA flux and MHC-I expression not resolved","Single lab"]},{"year":2024,"claim":"Demonstrated context-dependent pro-death signaling, with STAT3-induced ACSL5 driving lipoapoptosis in tubular cells in diabetic kidney disease.","evidence":"ACSL5 gain/loss in BUMPT cells, lipid and FFA assays, STAT3 knockdown rescue, promoter activity, and HFD/STZ mouse model","pmids":["39557186"],"confidence":"Medium","gaps":["Lipid species mediating apoptosis not pinpointed","Single lab"]},{"year":2025,"claim":"Expanded post-translational stabilization control by identifying OTUB1 as a second deubiquitinase sustaining ACSL5 and fatty acid oxidation in acute liver injury.","evidence":"MS substrate identification, Co-IP, ubiquitination assay, and OTUB1 gain/loss with FAO measurement","pmids":["40280245"],"confidence":"Medium","gaps":["Relationship between OTUB1 and USP29 regulation of the same target unclear","Single lab"]},{"year":2025,"claim":"Placed ACSL5 within a ferroptosis/apoptosis-resistance axis downstream of NPM1/SP1 in rhabdomyosarcoma, linking it to AURKB-targeted therapy response.","evidence":"AURKB inhibition with NPM1/SP1/ACSL5 epistasis and apoptosis/ferroptosis assays in vitro and in vivo","pmids":["39927464"],"confidence":"Medium","gaps":["How ACSL5 acyl-CoA products modulate ferroptosis lipid peroxidation not defined","Single lab"]},{"year":2025,"claim":"Uncovered a p53–ACSL5 feedback circuit reprogramming central metabolism under glutamine deprivation in colorectal cancer, coupling ACSL5 to oxaliplatin sensitivity.","evidence":"ACSL5 gain/loss, p53 ChIP, MDM2 stabilization, IDH2 and PGAM1 activity, ROS, and chemosensitivity assays","pmids":["41355704"],"confidence":"Medium","gaps":["Direct biochemistry of ACSL5–MDM2/MIB1 competition not structurally resolved","Single lab"]},{"year":2025,"claim":"Linked ACSL5-driven fatty acid oxidation to nuclear signaling via acetyl-CoA-dependent 53BP1 acetylation engaging p53-p21 senescence, and identified DNMT1 silencing in bladder cancer.","evidence":"ACSL5 gain/loss, acetyl-CoA and 53BP1-K1360 acetylation assays, DNMT1 knockdown, and tumor models","pmids":["40595416"],"confidence":"Medium","gaps":["Whether 53BP1 acetylation is a direct ACSL5-dependent event versus bulk acetyl-CoA effect not separated","Single lab"]},{"year":2025,"claim":"Added an interferon-gamma/IRF-1 transcriptional input and showed ACSL5 maintains ATP and reshapes the tubular cell lipidome by reducing ceramide and glycerolipid content.","evidence":"Multi-omics with IRF-1 perturbation and ACSL5 functional assays in kidney tubular cells and patient cohorts","pmids":["40546938"],"confidence":"Medium","gaps":["Direct IRF-1 binding to the ACSL5 promoter not shown","Single lab"]},{"year":2025,"claim":"Identified transcriptional repression of ACSL5 by a JAB1/CRL4B complex co-occupying its promoter in breast cancer, adding a negative regulatory arm.","evidence":"ChIP co-occupancy, CUL4B stabilization, gene expression and proliferation/invasion assays","pmids":["41388188"],"confidence":"Medium","gaps":["Mechanism by which CRL4B represses transcription at this locus unclear","Single lab"]},{"year":2026,"claim":"Showed ACSL5 enables metastatic adaptation to a palmitic acid–rich lung microenvironment through COX2/PGE2-EP4 activation of pro-survival signaling.","evidence":"ACSL5 gain/loss in breast cancer cells and mouse metastasis models, PGE2 measurement, signaling analysis, and 2-bromopalmitate treatment","pmids":["41570334"],"confidence":"Medium","gaps":["Link between ACSL5 acyl-CoA products and COX2 induction not mechanistically resolved","Single lab"]},{"year":null,"claim":"How the multiple post-translational (acetylation, K48 deubiquitination) and transcriptional inputs are integrated to set ACSL5 activity in a given tissue, and whether ACSL5 acyl-CoA products signal directly versus through bulk metabolite pools, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ACSL5 catalysis or regulation","Opposing E3 ligase(s) for USP29/OTUB1 not identified","Mechanistic link from acyl-CoA flux to MHC-I, ferroptosis, and senescence outputs not directly established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,7,15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,6]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,11]}],"complexes":[],"partners":["SIRT6","USP29","OTUB1","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULC5","full_name":"Long-chain-fatty-acid--CoA ligase 5","aliases":["Arachidonate--CoA ligase","Long-chain acyl-CoA synthetase 5","LACS 5"],"length_aa":683,"mass_kda":76.0,"function":"Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:17681178, PubMed:22633490, PubMed:24269233, PubMed:33191500). ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage (By similarity). Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids (By similarity). It was suggested that it may also stimulate fatty acid oxidation (By similarity). At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells","subcellular_location":"Mitochondrion; Endoplasmic reticulum; Mitochondrion outer membrane; Endoplasmic reticulum membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACSL5","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACSL5","total_profiled":1310},"omim":[{"mim_id":"621413","title":"PHOSPHOLIPASE A2 INHIBITOR AND LY6/PLAUR DOMAIN-CONTAINING PROTEIN; PINLYP","url":"https://www.omim.org/entry/621413"},{"mim_id":"620357","title":"DIARRHEA 13; DIAR13","url":"https://www.omim.org/entry/620357"},{"mim_id":"605677","title":"ACYL-CoA SYNTHETASE LONG CHAIN FAMILY, MEMBER 5; ACSL5","url":"https://www.omim.org/entry/605677"},{"mim_id":"604443","title":"ACYL-CoA SYNTHETASE LONG CHAIN FAMILY, MEMBER 6; ACSL6","url":"https://www.omim.org/entry/604443"},{"mim_id":"602550","title":"BRAIN AND MUSCLE ARNT-LIKE PROTEIN 1; BMAL1","url":"https://www.omim.org/entry/602550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"epididymis","ntpm":211.6},{"tissue":"intestine","ntpm":405.8},{"tissue":"liver","ntpm":159.5}],"url":"https://www.proteinatlas.org/search/ACSL5"},"hgnc":{"alias_symbol":["ACS5","ACS2"],"prev_symbol":["FACL5"]},"alphafold":{"accession":"Q9ULC5","domains":[{"cath_id":"3.40.50.980","chopping":"78-251","consensus_level":"high","plddt":95.9229,"start":78,"end":251},{"cath_id":"3.30.300.30","chopping":"546-681","consensus_level":"high","plddt":87.5747,"start":546,"end":681}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULC5-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACSL5","jax_strain_url":"https://www.jax.org/strain/search?query=ACSL5"},"sequence":{"accession":"Q9ULC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULC5"}},"corpus_meta":[{"pmid":"9722683","id":"PMC_9722683","title":"A novel acyl-CoA synthetase, ACS5, expressed in intestinal epithelial cells and proliferating preadipocytes.","date":"1998","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9722683","citation_count":130,"is_preprint":false},{"pmid":"36208627","id":"PMC_36208627","title":"Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/36208627","citation_count":86,"is_preprint":false},{"pmid":"36932115","id":"PMC_36932115","title":"Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36932115","citation_count":78,"is_preprint":false},{"pmid":"26977393","id":"PMC_26977393","title":"Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption.","date":"2016","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26977393","citation_count":77,"is_preprint":false},{"pmid":"27539148","id":"PMC_27539148","title":"The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5.","date":"2016","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/27539148","citation_count":62,"is_preprint":false},{"pmid":"38350448","id":"PMC_38350448","title":"Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.","date":"2024","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38350448","citation_count":59,"is_preprint":false},{"pmid":"32968195","id":"PMC_32968195","title":"A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32968195","citation_count":54,"is_preprint":false},{"pmid":"33113361","id":"PMC_33113361","title":"Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33113361","citation_count":53,"is_preprint":false},{"pmid":"17761945","id":"PMC_17761945","title":"Transcriptional activation of hepatic ACSL3 and ACSL5 by oncostatin m reduces hypertriglyceridemia through enhanced beta-oxidation.","date":"2007","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17761945","citation_count":53,"is_preprint":false},{"pmid":"25464840","id":"PMC_25464840","title":"Casein kinase 1 regulates ethylene synthesis by phosphorylating and promoting the turnover of ACS5.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25464840","citation_count":46,"is_preprint":false},{"pmid":"28122360","id":"PMC_28122360","title":"Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28122360","citation_count":44,"is_preprint":false},{"pmid":"30712446","id":"PMC_30712446","title":"LOX and ACSL5 as potential relapse markers for pancreatic cancer patients.","date":"2019","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30712446","citation_count":36,"is_preprint":false},{"pmid":"32129880","id":"PMC_32129880","title":"ONECUT2 upregulation is associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5.","date":"2020","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32129880","citation_count":31,"is_preprint":false},{"pmid":"38539505","id":"PMC_38539505","title":"The Diagnostic Value of ACSL1, ACSL4, and ACSL5 and the Clinical Potential of an ACSL Inhibitor in Non-Small-Cell Lung Cancer.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38539505","citation_count":25,"is_preprint":false},{"pmid":"29605434","id":"PMC_29605434","title":"ACSL5 genotype influence on fatty acid metabolism: a cellular, tissue, and whole-body study.","date":"2018","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/29605434","citation_count":20,"is_preprint":false},{"pmid":"22163040","id":"PMC_22163040","title":"High ACSL5 transcript levels associate with systemic lupus erythematosus and apoptosis in Jurkat T lymphocytes and peripheral blood cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22163040","citation_count":16,"is_preprint":false},{"pmid":"24770931","id":"PMC_24770931","title":"TP53 status regulates ACSL5-induced expression of mitochondrial mortalin in enterocytes and colorectal adenocarcinomas.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24770931","citation_count":15,"is_preprint":false},{"pmid":"39355870","id":"PMC_39355870","title":"USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination.","date":"2024","source":"Clinical and molecular hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39355870","citation_count":13,"is_preprint":false},{"pmid":"27189022","id":"PMC_27189022","title":"A splice variant in the ACSL5 gene relates migraine with fatty acid activation in mitochondria.","date":"2016","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/27189022","citation_count":11,"is_preprint":false},{"pmid":"38499083","id":"PMC_38499083","title":"Intestinal Acyl-CoA synthetase 5 (ACSL5) deficiency potentiates postprandial GLP-1 & PYY secretion, reduces food intake, and protects against diet-induced obesity.","date":"2024","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38499083","citation_count":9,"is_preprint":false},{"pmid":"24469710","id":"PMC_24469710","title":"Molecular cloning of the goose ACSL3 and ACSL5 coding domain sequences and their expression characteristics during goose fatty liver development.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24469710","citation_count":9,"is_preprint":false},{"pmid":"39557186","id":"PMC_39557186","title":"ACSL5 promotes lipid deposition and lipoapoptosis in proximal tubular epithelial cells of diabetic kidney disease.","date":"2024","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/39557186","citation_count":7,"is_preprint":false},{"pmid":"39357712","id":"PMC_39357712","title":"Structural characteristics of Lacticaseibacillus rhamnosus ACS5 exopolysaccharide in association with its antioxidant and antidiabetic activity in vitro.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39357712","citation_count":7,"is_preprint":false},{"pmid":"39927464","id":"PMC_39927464","title":"AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis.","date":"2025","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/39927464","citation_count":5,"is_preprint":false},{"pmid":"33106515","id":"PMC_33106515","title":"A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33106515","citation_count":5,"is_preprint":false},{"pmid":"40595416","id":"PMC_40595416","title":"ACSL5 regulated acetyl-CoA to promote bladder cancer cellular senescence via 53BP1 acetylation.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40595416","citation_count":4,"is_preprint":false},{"pmid":"30463708","id":"PMC_30463708","title":"Expression Analysis of ACSL5 and Wnt2B in Human Congenital Pulmonary Airway Malformations.","date":"2018","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/30463708","citation_count":4,"is_preprint":false},{"pmid":"40254111","id":"PMC_40254111","title":"Scutellariae Radix and Coptidis Rhizoma improve NAFLD via regulation of SIRT6/ACSL5 pathway and SCD1.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40254111","citation_count":3,"is_preprint":false},{"pmid":"37946526","id":"PMC_37946526","title":"Regulatory roles of ACSL5 in the anti-tumor function of palmitic acid (C16:0) <em>via</em> the ERK signaling pathway.","date":"2023","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/37946526","citation_count":3,"is_preprint":false},{"pmid":"40546938","id":"PMC_40546938","title":"Interferon gamma induced-ACSL5 shapes the lipidome of kidney tubular cells.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40546938","citation_count":2,"is_preprint":false},{"pmid":"41388188","id":"PMC_41388188","title":"JAB1/CRL4B complex represses PPARG/ACSL5 expression to promote breast tumorigenesis.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41388188","citation_count":1,"is_preprint":false},{"pmid":"40195491","id":"PMC_40195491","title":"ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40195491","citation_count":1,"is_preprint":false},{"pmid":"40280245","id":"PMC_40280245","title":"OTUB1 enhances fatty acid oxidation in APAP-induced liver injury by mediating ACSL5 deubiquitination.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40280245","citation_count":1,"is_preprint":false},{"pmid":"41355704","id":"PMC_41355704","title":"ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41355704","citation_count":0,"is_preprint":false},{"pmid":"41570334","id":"PMC_41570334","title":"ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.","date":"2026","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41570334","citation_count":0,"is_preprint":false},{"pmid":"42256738","id":"PMC_42256738","title":"Identification of a novel InDel locus within the ACSL5 gene and its association with body measurement traits in goats.","date":"2025","source":"Archives animal breeding","url":"https://pubmed.ncbi.nlm.nih.gov/42256738","citation_count":0,"is_preprint":false},{"pmid":"41572200","id":"PMC_41572200","title":"Novel homozygous variant in ACSL5 gene causing Congenital Diarrhea and Enteropathy (CODE) with sustained therapeutic success: a case report.","date":"2026","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41572200","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.13.642692","title":"Role of Long Chain Acyl-CoA Synthetases in MASH-driven Hepatocellular Carcinoma and Ferroptosis","date":"2025-03-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.13.642692","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22370,"output_tokens":6282,"usd":0.08067,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15115,"output_tokens":5086,"usd":0.101362,"stage2_stop_reason":"end_turn"},"total_usd":0.182032,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Rat ACS5 (ACSL5) is a long-chain acyl-CoA synthetase that activates a wide range of saturated fatty acids (C16–C18 range) with preference for C16–C18 unsaturated fatty acids; the purified recombinant enzyme produced in E. coli demonstrated this substrate specificity directly.\",\n      \"method\": \"Recombinant protein overproduction in E. coli, purification to near-homogeneity, in vitro enzymatic activity assay with fatty acid substrates\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified enzyme and substrate specificity profiling in a single rigorous study\",\n      \"pmids\": [\"9722683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Oncostatin M (OM) transcriptionally activates ACSL5 (and ACSL3) in hepatic cells through the ERK signaling pathway, and overexpression of ACSL5 alone partitions fatty acids toward beta-oxidation rather than triglyceride synthesis; siRNA knockdown of ACSL5 abrogated the OM-induced enhancement of fatty acid oxidation.\",\n      \"method\": \"Transcriptional activation assay in HepG2 cells and hamster liver, siRNA knockdown, fatty acid oxidation assay, ACSL5 overexpression\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function (overexpression + siRNA knockdown) with functional oxidation readout in both cell and animal models\",\n      \"pmids\": [\"17761945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ACSL5 knockout mice show ~80% reduction in ACSL activity in jejunal mucosa, reduced fat mass, increased energy expenditure, improved insulin sensitivity, elevated FGF21 (hepatic mRNA ~16-fold, serum ~13-fold), and delayed triglyceride absorption after olive oil gavage, establishing ACSL5 as a key regulator of intestinal fat absorption and whole-body energy metabolism.\",\n      \"method\": \"Whole-body ACSL5 knockout mouse model, ACSL enzyme activity assay, indirect calorimetry, olive oil gavage triglyceride absorption assay, insulin tolerance test, FGF21 measurement\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean whole-body KO with multiple orthogonal metabolic phenotypes and direct ACSL activity measurements\",\n      \"pmids\": [\"26977393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ACSL5 rs2419621 T allele is associated with higher levels of the 683-aa ACSL5 protein isoform (vs. the 739-aa isoform), which localizes predominantly to mitochondria and drives greater fatty acid oxidation; primary myotubes from T-allele carriers showed higher CO2 production from 14C-palmitic acid, and vastus lateralis biopsies showed higher mitochondrial complex I and II respiration.\",\n      \"method\": \"ACSL5 overexpression in C2C12 myoblasts, 14C-palmitic acid oxidation assay, subcellular localization by fractionation/Western blot, primary myotube respirometry, ex vivo mitochondrial high-resolution respirometry in human biopsies\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (14C oxidation, respirometry, localization), single lab, moderate sample sizes\",\n      \"pmids\": [\"29605434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The genomic region harboring the T2D-associated SNP rs7903146 within TCF7L2 functions as a regulatory element that physically contacts the ACSL5 promoter; CRISPR-mediated deletion of this region reduces ACSL5 mRNA up to 30-fold and abolishes chromatin contacts with the ACSL5 promoter, identifying rs7903146 as a cis-regulatory variant controlling ACSL5 expression.\",\n      \"method\": \"CRISPR/Cas9 deletion in HCT116, global gene expression analysis, 4C and Capture-C chromatin conformation capture\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — CRISPR functional deletion combined with two independent chromatin conformation methods (4C + Capture C) in multiple cell lines and tissue validation\",\n      \"pmids\": [\"27539148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cytoplasmic SIRT6 deacetylates ACSL5 upon binding to saturated fatty acids (especially palmitic acid), which triggers SIRT6 nuclear export; deacetylation of ACSL5 by SIRT6 facilitates fatty acid oxidation and suppresses NAFLD. NASH tissues show reduced cytoplasmic SIRT6 and increased ACSL5 acetylation. Overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific KO mice.\",\n      \"method\": \"Co-IP, deacetylation assay (SIRT6-ACSL5 interaction), deacetylation-mimic overexpression in Sirt6 liver KO mice, fatty acid oxidation assay, hepatic ACSL5 OE and KD in vivo, patient/mouse NASH tissue analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical deacetylation assay, gain/loss-of-function in vivo, deacetylation-mimic rescue, replicated in patient tissue and mouse model\",\n      \"pmids\": [\"36208627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatic ACSL5 overexpression suppresses high-fat diet-induced NAFLD while ACSL5 depletion exacerbates it, demonstrating ACSL5 is a pro-fatty acid oxidation enzyme in liver whose activity is rate-limiting for NAFLD progression.\",\n      \"method\": \"Hepatic ACSL5 overexpression and shRNA knockdown in mice, HFD-induced NAFLD model, lipid accumulation and liver histology\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — paired gain- and loss-of-function in vivo with well-defined disease phenotype, same study as SIRT6 deacetylation findings\",\n      \"pmids\": [\"36208627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ACSL5 overexpression in CaCo2 cells causes approximately 2-fold increase in mitochondrial mortalin (HSPA9), accompanied by disturbance of acyl-CoA/sphingolipid metabolism; this mitochondrial mortalin upregulation requires wild-type TP53 and is absent in cells with mutated TP53.\",\n      \"method\": \"Proteomics of isolated mitochondria from ACSL5 transfectants, tandem mass spectrometry lipid analysis, siRNA gene silencing, Western blotting, qRT-PCR in CaCo2, HEK293, Lovo, Colo320DM cells\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics, lipid MS, and siRNA in multiple cell lines, single lab\",\n      \"pmids\": [\"24770931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated silencing of ACSL5 in Jurkat T cells decreased PMA+Ionomycin-induced apoptosis to control levels and reduced mRNA expression of FAS, FASLG, and TNF, indicating ACSL5 promotes apoptosis in T lymphocytes.\",\n      \"method\": \"siRNA knockdown of ACSL5 in Jurkat T cells, flow cytometry apoptosis assay, qRT-PCR for apoptosis-related genes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean siRNA KD with functional apoptosis readout, single lab, single method for each endpoint\",\n      \"pmids\": [\"22163040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP29 interacts directly with ACSL5 and stabilizes it via K48-linked deubiquitination, preventing proteasomal degradation; the protective effect of USP29 on fatty acid beta-oxidation in MASLD is dependent on ACSL5.\",\n      \"method\": \"Co-IP, K48-linked ubiquitination assay, USP29 overexpression/deletion in mice and hepatocytes, ACSL5 rescue experiments, FAO gene expression\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by Co-IP, deubiquitination linkage characterized, ACSL5-dependence confirmed by rescue, single lab\",\n      \"pmids\": [\"39355870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL5 regulates MHC-I-mediated antigen presentation in tumor cells; elaidic acid (EA) is identified as a substrate/activator of ACSL5 that enhances MHC-I expression and sensitizes tumors to CD8+ T cell cytotoxicity and PD-1 blockade therapy.\",\n      \"method\": \"In vitro cytotoxicity assay with CD8+ T cells, in vivo tumor models, MHC-I expression analysis, ACSL5 substrate screening, ACSL5 overexpression/KD in tumor cells\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain/loss-of-function with defined immune readout and substrate identification, single lab, multiple methods\",\n      \"pmids\": [\"38350448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Intestine-specific ACSL5 knockout (ACSL5IKO) mice are protected from diet-induced obesity exclusively through reduced food intake; this is mechanistically driven by increased FA content in the distal small intestine that elevates postprandial GLP-1 and PYY secretion; GLP-1 receptor antagonism partially restored food intake in ACSL5IKO mice.\",\n      \"method\": \"Intestine-specific conditional KO (tamoxifen-inducible villin-Cre), metabolic phenotyping, GLP-1/PYY measurement after TAG challenge, GLP-1 receptor antagonist treatment, dietary fat absorption and fecal lipid excreion assays\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with receptor antagonist epistasis experiment and multiple orthogonal readouts, mechanistic pathway established\",\n      \"pmids\": [\"38499083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL5 promotes lipoapoptosis in proximal tubular epithelial cells in diabetic kidney disease; ACSL5 knockdown reduces lipid deposition and lipoapoptosis while overexpression exacerbates them. STAT3 transcriptionally activates the ACSL5 promoter under high-glucose/palmitic acid conditions.\",\n      \"method\": \"ACSL5 KD and OE in BUMPT cells, Oil Red O staining, FFA ELISA, Western blot, STAT3 KD with ACSL5 OE rescue, ACSL5 promoter activity assay, HFD/STZ mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function in vitro and in vivo, promoter activity validation, single lab\",\n      \"pmids\": [\"39557186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUB1 deubiquitinase interacts with ACSL5 and promotes its deubiquitination and protein stability, thereby enhancing fatty acid oxidation in APAP-induced acute liver injury; the protective effect of OTUB1 overexpression on FAO requires ACSL5.\",\n      \"method\": \"Mass spectrometry identification of ACSL5 as OTUB1 substrate, Co-IP, ubiquitination assay, OTUB1 OE/KD in vivo and in vitro, FAO measurement\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification, Co-IP, functional rescue, single lab\",\n      \"pmids\": [\"40280245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AURKB inhibition suppresses RMS cell growth by inducing apoptosis and ferroptosis through a NPM1/SP1/ACSL5 signaling axis; ACSL5 is downstream of NPM1 and SP1 in mediating ferroptosis and apoptosis resistance in rhabdomyosarcoma cells.\",\n      \"method\": \"AURKB inhibition in vitro and in vivo, epistasis analysis with NPM1/SP1/ACSL5 knockdown/overexpression, apoptosis and ferroptosis assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established with gain/loss-of-function and defined pathway, single lab\",\n      \"pmids\": [\"39927464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer cells under glutamine deprivation, ACSL5 is upregulated by p53 transcriptionally and in turn competes with MIB1 to stabilize MDM2, suppressing p53 in a feedback loop; ACSL5 mitochondrial localization activates IDH2 to accelerate the TCA cycle, while also relieving p53-mediated inhibition of PGAM1 to drive glycolysis; these metabolic changes generate ROS and sensitize cells to oxaliplatin.\",\n      \"method\": \"ACSL5 OE/KD in colorectal cancer cells, p53 ChIP and transcriptional assay, MDM2 stabilization assay, PGAM1 functional assay, IDH2 activity assay, ROS measurement, oxaliplatin sensitivity assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays in single lab, pathway placement by epistasis, single study\",\n      \"pmids\": [\"41355704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSL5 promotes fatty acid oxidation in bladder cancer cells; by enhancing FAO, ACSL5 increases intracellular acetyl-CoA levels, which in turn acetylate 53BP1 at K1360, enhancing recruitment of the p53-p21 senescence signaling axis in the nucleus and driving cellular senescence. ACSL5 expression is silenced in bladder cancer by DNMT1-mediated CpG island methylation.\",\n      \"method\": \"ACSL5 OE/KD, acetyl-CoA measurement, 53BP1 acetylation assay (K1360), p53-p21 pathway analysis, DNMT1 knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mechanistic linkage between ACSL5 activity, acetyl-CoA production, and 53BP1 acetylation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40595416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF-1 signaling (downstream of interferon-gamma) induces ACSL5 expression in kidney tubular cells; ACSL5 maintains ATP production and cell viability and shapes the lipid composition of tubular cells by reducing ceramide accumulation and glycerolipid content.\",\n      \"method\": \"Transcriptomic, metabolomic, and lipidomic analysis of experimental models and patient cohorts, IRF-1 signaling perturbation, ACSL5 functional assays in kidney tubular cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with functional validation in cellular models, single lab, corroborated in patient data\",\n      \"pmids\": [\"40546938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In breast cancer, JAB1 forms a transcriptional repressor complex with CRL4B (Cullin 4B-Ring E3 ligase) that co-occupies the promoters of PPARG and ACSL5, leading to their transcriptional repression and consequent activation of fatty acid metabolism.\",\n      \"method\": \"ChIP showing JAB1/CRL4B co-occupancy of ACSL5 promoter, CUL4B stabilization assay, gene expression analysis, proliferation/invasion assays with JAB1 manipulation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional promoter repression established, single lab\",\n      \"pmids\": [\"41388188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ONECUT2 (OC2) transcription factor directly activates ACSL5 expression in gastric cancer cells; ChIP-seq and RNA-seq analyses revealed OC2 binding to the ACSL5 locus, and stable OC2 transfection increased ACSL5 expression.\",\n      \"method\": \"Stable OC2 transfection in GC cells, ChIP-seq, RNA-seq, OC2 knockdown with shRNA, correlation of OC2 and ACSL5 mRNA levels in patient database\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq in gain/loss-of-function system, single lab\",\n      \"pmids\": [\"32129880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A splice variant of ACSL5 lacking exon 20 (ACSL5-Δ20) is causally linked to the migraine-associated SNP rs12355831; the functional variant rs2256368-G directly causes ~20–40% exon 20 skipping of ACSL5 mRNA, as shown by exon-skipping assay, implicating altered ACSL5 enzymatic activity (long-chain fatty acid activation) in mitochondria in migraine pathology.\",\n      \"method\": \"Exon-skipping assay, eQTL analysis in lymphoblastoid cell lines using GEUVADIS/1000 Genomes data\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — exon-skipping assay is direct, but functional consequence of the splice variant on ACSL5 enzyme activity was not measured; single lab\",\n      \"pmids\": [\"27189022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSL5 knockdown reversed the anti-tumor effects of palmitic acid (C16:0) in A549 lung cancer cells (increased proliferation, apoptosis resistance, migration, invasion), and C16:0 treatment upregulated ACSL5 expression while inhibiting phosphorylated ERK, placing ACSL5 downstream of palmitic acid signaling in the ERK pathway.\",\n      \"method\": \"ACSL5 siRNA knockdown in A549 cells, C16:0 treatment, CCK-8, annexin V/PI apoptosis assay, wound healing/transwell assay, Western blot for pERK, mouse xenograft model\",\n      \"journal\": \"European journal of histochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth, pathway placement inferred from expression changes without direct enzymatic assay\",\n      \"pmids\": [\"37946526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In lung-preferential metastatic breast cancer cells, ACSL5 mediates adaptation to the palmitic acid-enriched lung microenvironment by inducing COX2-mediated PGE2 accumulation, which activates PI3K/AKT and ERK signaling via EP4, promoting cancer cell survival and lung metastasis; ACSL5 also upregulates palmitoyltransferases to further enhance COX2 expression.\",\n      \"method\": \"ACSL5 gain/loss-of-function in breast cancer cell lines and mouse models, PGE2 measurement, signaling pathway analysis (PI3K/AKT, ERK), palmitoylation inhibitor (2-bromopalmitate) treatment, in vivo metastasis models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain/loss-of-function with defined mechanistic pathway in vitro and in vivo, single lab\",\n      \"pmids\": [\"41570334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SR-CR herbal components enhance ACSL5 activity via SIRT6-mediated deacetylation, promoting fatty acid oxidation; validated by surface plasmon resonance and molecular docking confirming constituent-protein interactions.\",\n      \"method\": \"Western blot, immunofluorescence, surface plasmon resonance, molecular docking, in vivo HFD rat model, HepG2 cell model\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — surface plasmon resonance and molecular docking for ligand binding, but direct ACSL5 deacetylation and enzymatic activity not separately measured; single lab\",\n      \"pmids\": [\"40254111\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSL5 is a mitochondria-associated long-chain acyl-CoA synthetase that activates long-chain fatty acids (preferring C16–C18 saturated and unsaturated species) to acyl-CoA thioesters, thereby directing fatty acids into beta-oxidation; its activity is positively regulated by SIRT6-mediated deacetylation and stabilized by USP29 and OTUB1 deubiquitination, while it is transcriptionally activated by oncostatin M (via ERK), IRF-1/interferon-gamma, p53, STAT3, and ONECUT2, and repressed by JAB1/CRL4B; in the intestine, ACSL5 controls long-chain fatty acid absorption and enteroendocrine (GLP-1/PYY) signaling; and in various tissues it modulates downstream processes including apoptosis, ferroptosis, cellular senescence (via acetyl-CoA-dependent 53BP1 acetylation), MHC-I antigen presentation, and tumor immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACSL5 is a long-chain acyl-CoA synthetase that activates C16–C18 fatty acids—with a preference for unsaturated species—to acyl-CoA thioesters, channeling fatty acids toward beta-oxidation rather than triglyceride synthesis [#0, #1]. Localizing predominantly to mitochondria, its activity is rate-limiting for hepatic fatty acid oxidation: overexpression suppresses diet-induced fatty liver while depletion exacerbates it [#3, #6]. In the intestine ACSL5 governs long-chain fatty acid absorption and whole-body energy balance, and its loss limits food intake by raising distal intestinal fatty acid content and potentiating GLP-1/PYY secretion [#2, #11]. ACSL5 protein levels and activity are tuned post-translationally—stabilized by USP29- and OTUB1-mediated deubiquitination [#9, #13] and activated by SIRT6-dependent deacetylation that licenses fatty acid oxidation and protects against fatty liver disease [#5]—and its transcription is driven by oncostatin M via ERK, IRF-1/interferon-gamma, STAT3, p53, and ONECUT2, while being repressed by a JAB1/CRL4B complex [#1, #17, #12, #15, #19, #18]. Through its control of fatty acid flux ACSL5 acts as a metabolic node in disease contexts, promoting apoptosis and lipoapoptosis [#8, #12], shaping ferroptosis sensitivity downstream of NPM1/SP1 [#14], enhancing MHC-I antigen presentation and tumor immunity [#10], and driving acetyl-CoA-dependent 53BP1 acetylation that engages p53-p21 senescence signaling [#16]. Regulatory variation at the ACSL5 locus, including a TCF7L2-region cis-regulatory element and the rs2419621 isoform-determining allele, links ACSL5 expression to fatty acid oxidation phenotypes and metabolic traits [#4, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the core biochemical identity of ACSL5 as a long-chain acyl-CoA synthetase and defined its substrate preference, answering what reaction the enzyme catalyzes.\",\n      \"evidence\": \"Recombinant rat enzyme purified from E. coli and assayed in vitro against fatty acid substrates\",\n      \"pmids\": [\"9722683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate profiling done with rat ortholog in vitro; tissue-specific substrate selectivity not addressed\", \"No structural basis for chain-length preference\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ACSL5 directs fatty acids into beta-oxidation rather than triglyceride synthesis and is transcriptionally induced by oncostatin M through ERK, connecting enzyme activity to a metabolic fate decision.\",\n      \"evidence\": \"Transcriptional activation, siRNA knockdown, overexpression and fatty acid oxidation assays in HepG2 cells and hamster liver\",\n      \"pmids\": [\"17761945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERK target on the ACSL5 promoter not mapped\", \"Did not establish in vivo physiological consequence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the in vivo physiological role of ACSL5 in intestinal fat absorption and whole-body energy metabolism, moving beyond cell-based oxidation readouts.\",\n      \"evidence\": \"Whole-body ACSL5 knockout mice with calorimetry, triglyceride absorption, insulin tolerance, and FGF21 measurements\",\n      \"pmids\": [\"26977393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whole-body KO cannot resolve tissue-of-origin for each phenotype\", \"Mechanism linking ACSL5 loss to FGF21 elevation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified genomic regulation of ACSL5 expression, showing a TCF7L2-region T2D-associated variant acts as a cis-regulatory element physically contacting the ACSL5 promoter.\",\n      \"evidence\": \"CRISPR deletion in HCT116 plus 4C and Capture-C chromatin conformation capture\",\n      \"pmids\": [\"27539148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional metabolic consequence of altered ACSL5 expression via this element not measured\", \"Relationship to TCF7L2 protein function not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked an ACSL5 coding/isoform variant to mitochondrial localization and fatty acid oxidation capacity in human tissue, connecting genotype to functional respirometry.\",\n      \"evidence\": \"Isoform overexpression in myoblasts, 14C-palmitate oxidation, subcellular fractionation, and human biopsy respirometry\",\n      \"pmids\": [\"29605434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, moderate sample size\", \"Mechanism by which the 683-aa isoform localizes preferentially to mitochondria not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed post-translational activation of ACSL5 by SIRT6-mediated deacetylation as a saturated-fatty-acid-responsive switch controlling fatty acid oxidation and fatty liver disease.\",\n      \"evidence\": \"Co-IP, deacetylation assay, deacetylation-mimic rescue in Sirt6 liver-KO mice, and NASH patient/mouse tissue analysis\",\n      \"pmids\": [\"36208627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation site(s) on ACSL5 and their effect on catalysis not fully mapped\", \"Coordination with deubiquitination control unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established deubiquitination as a second post-translational control point, with USP29 stabilizing ACSL5 against proteasomal degradation to sustain hepatic fatty acid oxidation.\",\n      \"evidence\": \"Co-IP, K48-linked ubiquitination assay, USP29 gain/loss in mice and hepatocytes with ACSL5 rescue\",\n      \"pmids\": [\"39355870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP29 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the cellular mechanism of ACSL5-dependent appetite control, showing intestinal ACSL5 loss limits food intake via distal fatty acid–driven GLP-1/PYY secretion.\",\n      \"evidence\": \"Intestine-specific inducible KO with GLP-1/PYY measurement and GLP-1 receptor antagonist epistasis\",\n      \"pmids\": [\"38499083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sensing mechanism translating luminal fatty acids into enteroendocrine secretion not detailed\", \"Contribution of PYY versus GLP-1 not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ACSL5 fatty acid metabolism to tumor immunity by showing it regulates MHC-I antigen presentation and CD8+ T cell sensitivity, with elaidic acid as an activating substrate.\",\n      \"evidence\": \"CD8+ T cell cytotoxicity, in vivo tumor models, MHC-I analysis, and ACSL5 substrate screening with gain/loss-of-function\",\n      \"pmids\": [\"38350448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between acyl-CoA flux and MHC-I expression not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated context-dependent pro-death signaling, with STAT3-induced ACSL5 driving lipoapoptosis in tubular cells in diabetic kidney disease.\",\n      \"evidence\": \"ACSL5 gain/loss in BUMPT cells, lipid and FFA assays, STAT3 knockdown rescue, promoter activity, and HFD/STZ mouse model\",\n      \"pmids\": [\"39557186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipid species mediating apoptosis not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded post-translational stabilization control by identifying OTUB1 as a second deubiquitinase sustaining ACSL5 and fatty acid oxidation in acute liver injury.\",\n      \"evidence\": \"MS substrate identification, Co-IP, ubiquitination assay, and OTUB1 gain/loss with FAO measurement\",\n      \"pmids\": [\"40280245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between OTUB1 and USP29 regulation of the same target unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ACSL5 within a ferroptosis/apoptosis-resistance axis downstream of NPM1/SP1 in rhabdomyosarcoma, linking it to AURKB-targeted therapy response.\",\n      \"evidence\": \"AURKB inhibition with NPM1/SP1/ACSL5 epistasis and apoptosis/ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"39927464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ACSL5 acyl-CoA products modulate ferroptosis lipid peroxidation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a p53–ACSL5 feedback circuit reprogramming central metabolism under glutamine deprivation in colorectal cancer, coupling ACSL5 to oxaliplatin sensitivity.\",\n      \"evidence\": \"ACSL5 gain/loss, p53 ChIP, MDM2 stabilization, IDH2 and PGAM1 activity, ROS, and chemosensitivity assays\",\n      \"pmids\": [\"41355704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemistry of ACSL5–MDM2/MIB1 competition not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ACSL5-driven fatty acid oxidation to nuclear signaling via acetyl-CoA-dependent 53BP1 acetylation engaging p53-p21 senescence, and identified DNMT1 silencing in bladder cancer.\",\n      \"evidence\": \"ACSL5 gain/loss, acetyl-CoA and 53BP1-K1360 acetylation assays, DNMT1 knockdown, and tumor models\",\n      \"pmids\": [\"40595416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether 53BP1 acetylation is a direct ACSL5-dependent event versus bulk acetyl-CoA effect not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added an interferon-gamma/IRF-1 transcriptional input and showed ACSL5 maintains ATP and reshapes the tubular cell lipidome by reducing ceramide and glycerolipid content.\",\n      \"evidence\": \"Multi-omics with IRF-1 perturbation and ACSL5 functional assays in kidney tubular cells and patient cohorts\",\n      \"pmids\": [\"40546938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IRF-1 binding to the ACSL5 promoter not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified transcriptional repression of ACSL5 by a JAB1/CRL4B complex co-occupying its promoter in breast cancer, adding a negative regulatory arm.\",\n      \"evidence\": \"ChIP co-occupancy, CUL4B stabilization, gene expression and proliferation/invasion assays\",\n      \"pmids\": [\"41388188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CRL4B represses transcription at this locus unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed ACSL5 enables metastatic adaptation to a palmitic acid–rich lung microenvironment through COX2/PGE2-EP4 activation of pro-survival signaling.\",\n      \"evidence\": \"ACSL5 gain/loss in breast cancer cells and mouse metastasis models, PGE2 measurement, signaling analysis, and 2-bromopalmitate treatment\",\n      \"pmids\": [\"41570334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between ACSL5 acyl-CoA products and COX2 induction not mechanistically resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple post-translational (acetylation, K48 deubiquitination) and transcriptional inputs are integrated to set ACSL5 activity in a given tissue, and whether ACSL5 acyl-CoA products signal directly versus through bulk metabolite pools, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ACSL5 catalysis or regulation\", \"Opposing E3 ligase(s) for USP29/OTUB1 not identified\", \"Mechanistic link from acyl-CoA flux to MHC-I, ferroptosis, and senescence outputs not directly established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 7, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SIRT6\", \"USP29\", \"OTUB1\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}