{"gene":"ACSL5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1998,"finding":"ACSL5 (rat ACS5) is a novel long-chain acyl-CoA synthetase that activates a wide range of saturated fatty acids (C10–C18) and shows a distinct preference for C16–C18 unsaturated fatty acids (oleate, arachidonate, EPA, DHA) compared to ACS1/ACS2, as demonstrated by purification from E. coli and enzymatic characterization.","method":"Recombinant protein overexpression in E. coli, purification to homogeneity, enzymatic activity assay with various fatty acid substrates","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic reconstitution with purified recombinant protein and substrate profiling","pmids":["9722683"],"is_preprint":false},{"year":2007,"finding":"Oncostatin M (OM) activates transcription of ACSL5 (and ACSL3) in hepatocytes through the ERK signaling pathway, and overexpression of ACSL5 alone partitions fatty acids into β-oxidation, reducing triglyceride accumulation; siRNA knockdown of ACSL5 abrogates OM-enhanced fatty acid oxidation.","method":"Transcriptional reporter assays, siRNA knockdown, overexpression in HepG2 cells, fatty acid oxidation assays, in vivo hamster model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (OE, KD, in vivo) establishing ACSL5's role in fatty acid β-oxidation downstream of ERK signaling","pmids":["17761945"],"is_preprint":false},{"year":2016,"finding":"Whole-body ACSL5 knockout mice show ~80% reduction in jejunal ACSL activity, reduced fat mass, increased energy expenditure, improved insulin sensitivity, delayed dietary triglyceride absorption after olive oil gavage, and markedly elevated hepatic and serum FGF21 levels (~16-fold and ~13-fold, respectively), establishing ACSL5 as a key regulator of intestinal fat absorption and whole-body energy metabolism.","method":"Conditional/whole-body knockout mouse model, indirect calorimetry, insulin tolerance test, oral fat gavage/triglyceride appearance assay, ACSL activity assays, FGF21 quantification","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined metabolic phenotypes and mechanistic readouts","pmids":["26977393"],"is_preprint":false},{"year":2016,"finding":"The TCF7L2 type 2 diabetes risk variant rs7903146 resides in a regulatory element that physically contacts the ACSL5 promoter (demonstrated by 4C and Capture-C); CRISPR deletion of this region reduces ACSL5 mRNA up to 30-fold and abolishes chromatin contacts with the ACSL5 promoter, identifying ACSL5 as the gene under the influence of this diabetes-associated variant.","method":"CRISPR/Cas9 deletion, global gene expression analysis, circularized chromosome conformation capture (4C), Capture-C, Western blot","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR deletion plus chromatin conformation capture with multiple deletion sizes confirming result","pmids":["27539148"],"is_preprint":false},{"year":2018,"finding":"The rs2419621 T allele of ACSL5 is associated with higher levels of the 683 aa ACSL5 protein isoform, which localizes predominantly to mitochondria (vs. the 739 aa isoform), and drives greater fatty acid oxidation in C2C12 myoblasts overexpressing human ACSL5, in primary rectus abdominis myotubes from T-allele carriers, and increased complex I/II respiration in vastus lateralis biopsies.","method":"14C palmitic acid oxidation, Western blot, subcellular localization by overexpression in C2C12 cells, high-resolution respirometry on muscle biopsies","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro, ex vivo, tissue) but single lab study with small sample sizes","pmids":["29605434"],"is_preprint":false},{"year":2022,"finding":"SIRT6 binds saturated fatty acids (especially palmitic acid), which triggers its nuclear export to the cytoplasm where it directly deacetylates ACSL5, enhancing ACSL5-mediated fatty acid β-oxidation; hepatic overexpression of a deacetylated ACSL5 mimic attenuates NAFLD in Sirt6 liver-specific knockout mice, and NASH tissues show reduced cytoplasmic SIRT6 and increased ACSL5 acetylation.","method":"Co-immunoprecipitation, subcellular fractionation, deacetylation assays, hepatic overexpression/depletion in mouse models, deacetylation-mimic rescue experiments, patient tissue analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical and in vivo methods with mechanistic rescue experiments in a single comprehensive study","pmids":["36208627"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated silencing of ACSL5 in Jurkat T cells decreases PMA/ionomycin-induced apoptosis to control levels and reduces mRNA expression of FAS, FASLG, and TNF, establishing a pro-apoptotic role for ACSL5 in T lymphocytes.","method":"siRNA knockdown, apoptosis assay, quantitative RT-PCR for apoptosis-related genes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined apoptotic phenotype and gene expression readouts, single lab","pmids":["22163040"],"is_preprint":false},{"year":2014,"finding":"ACSL5 overexpression in CaCo2 cells induces ~2-fold increase of mortalin (HSPA9) specifically in mitochondria (not cytoplasm), mediated through disturbance of acyl-CoA/sphingolipid metabolism; this mitochondrial mortalin upregulation is dependent on wild-type TP53 status and is observed in normal intestinal mucosa with an increasing gradient from crypt to villus tip.","method":"Mitochondrial proteomics of ACSL5 transfectants vs. CaCo2 controls, Western blot, siRNA knockdown, tandem mass spectrometry lipid analysis, immunohistochemistry of normal mucosa and adenocarcinomas","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus multiple validation methods, but single lab","pmids":["24770931"],"is_preprint":false},{"year":2016,"finding":"A functional variant rs2256368:A>G causes skipping of exon 20 in ACSL5 transcripts (ACSL5-Δ20) in ~20–40% of RNA molecules, as demonstrated by an exon-skipping assay; this splice variant is linked to the migraine-associated variant rs12355831, implicating altered mitochondrial long-chain fatty acid activation in migraine pathology.","method":"eQTL analysis of GEUVADIS RNA-seq data, exon-skipping assay with direct causality demonstration","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct exon-skipping assay demonstrates functional causality of the variant, but mechanistic downstream consequences are inferred","pmids":["27189022"],"is_preprint":false},{"year":2020,"finding":"A 103.3 kb deletion encompassing the ACSL5 gene (and ZDHHC6) in Australian Kelpie dogs causes complete absence of ACSL5 expression in jejunal tissue and results in intestinal lipid malabsorption, steatorrhea, and stunted growth, establishing ACSL5 as essential for intestinal long-chain fatty acid absorption in vivo.","method":"Genome-wide association analysis, whole transcriptomic sequencing confirming absent ACSL5 expression, PCR-based diagnostic test, autosomal recessive inheritance confirmation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — natural loss-of-function model with transcriptomic confirmation and clear phenotypic readout","pmids":["33106515"],"is_preprint":false},{"year":2024,"finding":"ACSL5 regulates MHC-I-mediated antigen presentation; ACSL5 expression sensitizes tumors to PD-1 blockade and to CD8+ T cell cytotoxicity in vitro, and elaidic acid (a trans LCFA) phenocopies ACSL5 to enhance MHC-I expression and suppress tumor growth in vivo.","method":"In vivo PD-1 blockade tumor models, in vitro CD8+ T cell cytotoxicity assays, ACSL5 substrate screening, MHC-I expression assays, dietary supplementation experiments","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro and in vivo orthogonal methods establishing ACSL5's mechanistic role in antigen presentation","pmids":["38350448"],"is_preprint":false},{"year":2024,"finding":"USP29 directly interacts with ACSL5 and stabilizes it by promoting K48-linked deubiquitination, thereby preventing proteasomal degradation of ACSL5; loss of USP29 reduces ACSL5 levels and fatty acid β-oxidation, exacerbating hepatic steatosis in MASLD, while the hepatoprotective effect of USP29 overexpression is dependent on ACSL5.","method":"Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), USP29 KO and OE in mice and hepatocytes, rescue experiments with ACSL5","journal":"Clinical and molecular hepatology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding demonstrated by Co-IP, K48 deubiquitination mechanistically characterized, in vivo rescue experiment","pmids":["39355870"],"is_preprint":false},{"year":2024,"finding":"Intestine-specific ACSL5 knockout (ACSL5IKO) mice are protected from diet-induced obesity exclusively through reduced food intake during high-fat feeding; loss of intestinal ACSL5 increases fatty acid content in the distal small intestine, elevates postprandial GLP-1 and PYY secretion, and GLP-1 receptor antagonism partially restores food intake, demonstrating that intestinal ACSL5 regulates energy balance via enteroendocrine signaling.","method":"Tamoxifen-inducible intestine-specific Cre knockout mouse model, metabolic phenotyping, GLP-1/PYY measurement after TAG challenge, GLP-1 receptor antagonist treatment, dietary fat absorption studies","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with mechanistic rescue (receptor antagonist), multiple orthogonal metabolic readouts","pmids":["38499083"],"is_preprint":false},{"year":2024,"finding":"STAT3 transcriptionally activates ACSL5 under high glucose/palmitic acid conditions by binding the ACSL5 promoter; ACSL5 promotes lipid deposition and lipoapoptosis in proximal tubular epithelial cells, and concurrent STAT3 knockdown with ACSL5 overexpression mitigates lipoapoptosis compared to ACSL5 overexpression alone.","method":"ChEA3 database prediction, STAT3 knockdown with RT-qPCR, promoter activation assay, ACSL5 KD and OE in BUMPT cells with Oil Red O staining, FFA ELISA, Western blot, diabetic mouse model","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 — promoter activation and rescue experiments, but single lab with partial mechanistic follow-up","pmids":["39557186"],"is_preprint":false},{"year":2025,"finding":"OTUB1 directly interacts with ACSL5 (identified by mass spectrometry), deubiquitinates ACSL5, and promotes its stability; OTUB1 overexpression improves fatty acid oxidation and alleviates APAP-induced liver injury in vivo and in vitro, and this protective effect on FAO is abolished when ACSL5 is co-depleted.","method":"Mass spectrometry identification of ACSL5 as OTUB1 substrate, Co-IP, deubiquitination assay, OTUB1 OE/KD in mice and hepatocytes, ACSL5 rescue/co-depletion experiments","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 — MS-based substrate identification, Co-IP, in vitro deubiquitination, in vivo rescue, single comprehensive study","pmids":["40280245"],"is_preprint":false},{"year":2025,"finding":"ACSL5 promotes fatty acid oxidation in colorectal cancer cells, operates within a p53 regulatory loop (p53 transcriptionally upregulates ACSL5; ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53), relieves p53-mediated inhibition of PGAM1 to drive glycolysis, and its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle.","method":"ACSL5 KD/OE in colorectal cancer cells, metabolic flux assays (glycolysis, OXPHOS), Co-IP (ACSL5-MIB1-MDM2 competition), p53 transcriptional reporter assays, PGAM1 activity assay, ROS measurement, oxaliplatin sensitivity assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway placement experiments in a single study, but not yet independently replicated","pmids":["41355704"],"is_preprint":false},{"year":2025,"finding":"ACSL5 promotes cellular senescence in bladder cancer by increasing acetyl-CoA production through fatty acid oxidation; elevated acetyl-CoA drives K1360 acetylation of 53BP1, enhancing recruitment of the p53-p21 senescent signaling axis to the nucleus; DNMT1-mediated CpG methylation silences ACSL5 in bladder cancer.","method":"ACSL5 OE/KD in bladder cancer cells, acetyl-CoA measurement, 53BP1 acetylation assay (K1360 site), p53-p21 pathway analysis, DNMT1 inhibition, in vitro and in vivo senescence assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway from ACSL5 → acetyl-CoA → 53BP1 acetylation → senescence established with multiple methods, single lab","pmids":["40595416"],"is_preprint":false},{"year":2025,"finding":"JAB1 forms a transcriptional repressor complex with CUL4B (CRL4B) that co-occupies the promoters of PPARG and ACSL5, leading to their transcriptional repression; JAB1 promotes breast cancer cell proliferation, invasion, and stemness by stabilizing CUL4B and suppressing ACSL5-mediated fatty acid metabolism.","method":"ChIP assay for CRL4B complex at PPARG/ACSL5 promoters, CUL4B stabilization assay, JAB1 OE/KD in breast cancer cells with proliferation/invasion/stemness readouts","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter co-occupancy, functional consequences validated, single lab","pmids":["41388188"],"is_preprint":false},{"year":2025,"finding":"ACSL5 expression is induced in kidney tubular cells via IRF-1 signaling (part of a gamma interferon-related gene signature); ACSL5 maintains ATP production and cell viability and shapes the tubular cell lipidome by reducing ceramide accumulation and modulating glycerolipid content.","method":"Transcriptomic, metabolomic, and lipidomic analyses of experimental models and patient cohorts; IRF-1 signaling manipulation in kidney tubular cells; cell viability and ATP assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with experimental validation in tubular cells, single lab","pmids":["40546938"],"is_preprint":false},{"year":2025,"finding":"AURKB inhibition in rhabdomyosarcoma reduces NPM1, which decreases SP1 transcription factor activity, leading to reduced ACSL5 expression; loss of ACSL5 promotes apoptosis and ferroptosis in RMS cells, establishing an AURKB/NPM1/SP1/ACSL5 axis in apoptosis/ferroptosis resistance.","method":"AURKB inhibitor treatment, NPM1/SP1/ACSL5 KD in RMS cells, apoptosis and ferroptosis assays in vitro, xenograft tumor growth assays in vivo","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established with sequential KD experiments and defined ferroptosis/apoptosis readouts, single lab","pmids":["39927464"],"is_preprint":false},{"year":2025,"finding":"ACSL5 in lung-metastatic breast cancer cells facilitates adaptation to palmitic acid (PA) enriched in the pulmonary microenvironment by inducing COX2-mediated PGE2 accumulation and activating PI3K/AKT and ERK signaling through EP4; ACSL5 also boosts palmitoyltransferase levels to further enhance COX2 expression, and this axis can be blocked by the palmitoylation inhibitor 2-bromopalmitate.","method":"ACSL5 OE/KD in breast cancer cell lines, COX2/PGE2 measurement, EP4 signaling assays, palmitoyltransferase activity assays, 2-bromopalmitate inhibition, breast cancer mouse metastasis models, patient tumor analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway components validated in vitro and in vivo, single lab","pmids":["41570334"],"is_preprint":false},{"year":2020,"finding":"The ONECUT2 (OC2) transcription factor directly activates ACSL5 transcription in gastric cancer cells, as shown by ChIP-seq and RNA-seq; OC2 upregulation (driven by promoter hypomethylation) triggers ACSL5 expression in intestinal metaplasia and gastric cancer, and OC2 knockdown suppresses tumorigenesis in nude mice.","method":"ChIP-seq, RNA-seq, stable transfection/knockdown of OC2, bisulfite sequencing for methylation, xenograft tumorigenesis assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq demonstrates direct transcriptional activation, functional KD in vivo, single lab","pmids":["32129880"],"is_preprint":false}],"current_model":"ACSL5 is a mitochondria-associated long-chain acyl-CoA synthetase that activates long-chain fatty acids to acyl-CoA thioesters, directing them toward β-oxidation and lipid metabolism; its activity and stability are regulated post-translationally by SIRT6-mediated deacetylation (enhancing activity), K48-linked ubiquitination/deubiquitination by USP29 and OTUB1, and transcriptionally by ERK/oncostatin M, STAT3, and OC2 signaling, while in the intestine ACSL5 is the dominant ACSL isoform controlling dietary fat absorption and enteroendocrine GLP-1/PYY secretion, and in cancer cells it modulates MHC-I antigen presentation, ferroptosis sensitivity, cellular senescence via acetyl-CoA/53BP1 acetylation, and metabolic adaptation to nutrient stress."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the enzymatic identity of ACSL5: purified recombinant protein demonstrated it is a long-chain acyl-CoA synthetase with a distinct substrate profile (C10–C18, preferring C16–C18 unsaturated fatty acids), distinguishing it from other ACSL family members.","evidence":"Recombinant overexpression in E. coli, purification to homogeneity, enzymatic activity assays with diverse fatty acid substrates","pmids":["9722683"],"confidence":"High","gaps":["No determination of subcellular localization","No tissue expression data beyond initial cloning","Kinetic parameters for all substrates not fully resolved"]},{"year":2007,"claim":"Linking ACSL5 to fatty acid β-oxidation and transcriptional regulation: oncostatin M induces ACSL5 via ERK signaling in hepatocytes, and ACSL5 overexpression preferentially channels fatty acids into β-oxidation rather than triglyceride storage, a function abolished by siRNA knockdown.","evidence":"Transcriptional reporter assays, siRNA knockdown, overexpression in HepG2 cells, fatty acid oxidation assays, in vivo hamster model","pmids":["17761945"],"confidence":"High","gaps":["Mechanism by which ACSL5 preferentially directs acyl-CoA to β-oxidation versus other fates not defined","ERK-responsive cis-regulatory element not mapped"]},{"year":2011,"claim":"Revealing a pro-apoptotic role in lymphocytes: ACSL5 silencing reduced activation-induced apoptosis and downregulated FAS/FASLG/TNF expression in T cells, expanding ACSL5 function beyond metabolic channeling.","evidence":"siRNA knockdown in Jurkat T cells, apoptosis assays, RT-qPCR for death receptor ligands","pmids":["22163040"],"confidence":"Medium","gaps":["Mechanism linking acyl-CoA production to death receptor gene transcription unknown","Not confirmed in primary T cells","No lipid metabolite analysis"]},{"year":2014,"claim":"Connecting ACSL5 to mitochondrial proteome remodeling: ACSL5 overexpression specifically upregulated mitochondrial mortalin (HSPA9) through altered acyl-CoA/sphingolipid metabolism in a p53-dependent manner, linking ACSL5 activity to mitochondrial stress responses.","evidence":"Mitochondrial proteomics, Western blot, siRNA knockdown, tandem mass spectrometry lipidomics in CaCo2 cells","pmids":["24770931"],"confidence":"Medium","gaps":["Direct mechanism for sphingolipid-driven mortalin induction not established","Single cell line","Functional consequence of mortalin upregulation not tested"]},{"year":2016,"claim":"Establishing ACSL5 as the dominant intestinal ACSL and a regulator of whole-body energy metabolism: ACSL5-knockout mice exhibited ~80% loss of jejunal ACSL activity, delayed fat absorption, reduced adiposity, improved insulin sensitivity, and massively elevated FGF21, while a linked genetic study demonstrated that a functional splice variant (exon 20 skipping) alters ACSL5 activity.","evidence":"Whole-body knockout mouse with indirect calorimetry, oral fat gavage, insulin tolerance tests, FGF21 quantification; eQTL and exon-skipping assay for splice variant","pmids":["26977393","27189022"],"confidence":"High","gaps":["Whether the metabolic phenotype is entirely intestine-autonomous was not resolved (whole-body KO)","Direct substrates and acyl-CoA species altered in intestinal epithelium not profiled"]},{"year":2016,"claim":"Linking the TCF7L2 type 2 diabetes risk locus to ACSL5 regulation: CRISPR deletion of the rs7903146-containing regulatory element reduced ACSL5 mRNA up to 30-fold and abolished chromatin contacts with the ACSL5 promoter, establishing ACSL5 as a target gene of this diabetes-associated variant.","evidence":"CRISPR/Cas9 deletion, 4C and Capture-C chromatin conformation capture, gene expression profiling","pmids":["27539148"],"confidence":"High","gaps":["Functional consequence of reduced ACSL5 in the cell types relevant to diabetes (β-cells, intestine) not tested","Whether ACSL5 reduction mediates the diabetes risk phenotype not proven"]},{"year":2018,"claim":"Demonstrating isoform-specific localization and function: the shorter 683 aa ACSL5 isoform (favored by the rs2419621 T allele) preferentially localizes to mitochondria and drives greater fatty acid oxidation and mitochondrial respiration compared to the longer isoform.","evidence":"14C palmitate oxidation in C2C12 myoblasts, subcellular localization, high-resolution respirometry on human muscle biopsies","pmids":["29605434"],"confidence":"Medium","gaps":["Structural basis for differential mitochondrial targeting of the two isoforms not defined","Small human sample size"]},{"year":2020,"claim":"Confirming ACSL5 is essential for intestinal fat absorption in a natural loss-of-function model: a homozygous deletion encompassing ACSL5 in dogs caused complete loss of jejunal ACSL5 expression, steatorrhea, and stunted growth, phenocopying the mouse knockout.","evidence":"GWAS, whole transcriptomic sequencing, autosomal recessive inheritance confirmation in Australian Kelpie dogs","pmids":["33106515"],"confidence":"Medium","gaps":["Deletion also removes ZDHHC6, so contribution of ZDHHC6 loss to phenotype not excluded","No biochemical characterization of residual ACSL activity"]},{"year":2020,"claim":"Identifying a direct transcriptional activator in gastric tissue: ONECUT2 binds the ACSL5 promoter and activates its transcription, with OC2 promoter hypomethylation driving ACSL5 upregulation in intestinal metaplasia and gastric cancer.","evidence":"ChIP-seq, RNA-seq, OC2 knockdown/overexpression, bisulfite sequencing, xenograft tumorigenesis","pmids":["32129880"],"confidence":"Medium","gaps":["Whether ACSL5 is the key downstream mediator of OC2 oncogenic effects not formally tested by ACSL5 rescue","Mechanism linking ACSL5 to gastric tumorigenesis not defined"]},{"year":2022,"claim":"Establishing a post-translational activation mechanism: SIRT6, triggered by palmitic acid binding, translocates to the cytoplasm and directly deacetylates ACSL5, enhancing its enzymatic activity; a deacetylation-mimic ACSL5 mutant rescues NAFLD in Sirt6-deficient livers.","evidence":"Co-immunoprecipitation, deacetylation assays, subcellular fractionation, hepatic overexpression/depletion in mice, deacetylation-mimic rescue, human NASH tissue analysis","pmids":["36208627"],"confidence":"High","gaps":["Specific acetylation sites on ACSL5 targeted by SIRT6 not fully mapped","Whether SIRT6-ACSL5 axis operates in non-hepatic tissues not tested"]},{"year":2024,"claim":"Resolving the intestine-autonomous mechanism: intestine-specific ACSL5 knockout protected mice from diet-induced obesity exclusively through reduced food intake; loss of ACSL5 increased distal intestinal fatty acid content, elevated postprandial GLP-1/PYY, and GLP-1 receptor antagonism partially reversed the anorectic phenotype.","evidence":"Tamoxifen-inducible intestine-specific Cre knockout, metabolic phenotyping, GLP-1/PYY measurement, GLP-1R antagonist rescue","pmids":["38499083"],"confidence":"High","gaps":["How unesterified fatty acids reaching the distal intestine stimulate enteroendocrine cells not molecularly defined","Whether ACSL5 inhibition in humans would recapitulate anorexigenic effects unknown"]},{"year":2024,"claim":"Expanding ACSL5 into cancer immunology: ACSL5 enhances MHC-I antigen presentation, sensitizing tumors to PD-1 blockade and CD8+ T cell killing; the trans fatty acid elaidic acid phenocopies ACSL5 to boost MHC-I expression and suppress tumor growth in vivo.","evidence":"In vivo tumor models with PD-1 blockade, CD8+ T cell cytotoxicity assays, ACSL5 substrate screening, dietary elaidic acid supplementation","pmids":["38350448"],"confidence":"High","gaps":["Lipid species mediating MHC-I upregulation not identified","Whether effect generalizes across tumor types not established"]},{"year":2024,"claim":"Defining a ubiquitin-mediated stability control mechanism: USP29 directly binds and deubiquitinates ACSL5 via K48-linked chains, preventing proteasomal degradation; loss of USP29 reduces ACSL5 levels and β-oxidation, worsening hepatic steatosis, while USP29 overexpression is hepatoprotective in an ACSL5-dependent manner.","evidence":"Co-immunoprecipitation, K48-linkage-specific ubiquitination assays, USP29 KO and OE in mice and hepatocytes, ACSL5 rescue experiments","pmids":["39355870"],"confidence":"High","gaps":["Specific ubiquitin sites on ACSL5 not mapped","E3 ligase responsible for K48 ubiquitination of ACSL5 not identified"]},{"year":2025,"claim":"A second deubiquitinase (OTUB1) was identified as a direct ACSL5 stabilizer by mass spectrometry, paralleling USP29; OTUB1-mediated ACSL5 stabilization improves fatty acid oxidation and protects against APAP-induced liver injury in an ACSL5-dependent manner.","evidence":"Mass spectrometry substrate identification, Co-IP, deubiquitination assay, OTUB1 OE/KD in mice and hepatocytes, ACSL5 co-depletion rescue","pmids":["40280245"],"confidence":"High","gaps":["Whether USP29 and OTUB1 act redundantly or in different contexts not resolved","Structural basis of OTUB1–ACSL5 interaction unknown"]},{"year":2025,"claim":"In cancer, ACSL5 operates at a metabolic–signaling nexus: it promotes senescence in bladder cancer by generating acetyl-CoA that acetylates 53BP1-K1360 to activate the p53–p21 axis; in colorectal cancer it stabilizes MDM2 by competing with MIB1, suppressing p53, and activates glycolysis (PGAM1) and TCA cycle (IDH2); in rhabdomyosarcoma it confers ferroptosis resistance downstream of AURKB/NPM1/SP1; and in metastatic breast cancer it fuels COX2/PGE2 signaling via palmitoylation to activate PI3K/AKT and ERK through EP4.","evidence":"ACSL5 OE/KD across bladder, colorectal, rhabdomyosarcoma, and breast cancer cell lines; acetyl-CoA and 53BP1 acetylation assays; Co-IP for MIB1–MDM2 competition; ferroptosis and apoptosis assays; COX2/PGE2 measurement; in vivo xenograft and metastasis models","pmids":["40595416","41355704","39927464","41570334"],"confidence":"Medium","gaps":["Many cancer-specific mechanisms reported by single labs and not yet independently replicated","Whether these diverse downstream effects all stem from acyl-CoA channeling or involve non-catalytic ACSL5 functions is unclear","Context-dependent tumor-suppressive versus oncogenic roles not reconciled"]},{"year":2025,"claim":"Additional transcriptional regulators of ACSL5 identified: STAT3 activates ACSL5 under diabetic conditions to promote lipoapoptosis in kidney tubular cells; JAB1–CRL4B represses ACSL5 at its promoter in breast cancer to suppress fatty acid metabolism; IRF-1 induces ACSL5 in kidney tubular cells to maintain ATP production and modulate the lipidome.","evidence":"ChIP for CRL4B at ACSL5 promoter; STAT3 promoter activation assay and KD/OE rescue in kidney cells; transcriptomic/lipidomic analysis with IRF-1 manipulation","pmids":["39557186","41388188","40546938"],"confidence":"Medium","gaps":["Direct STAT3 binding to ACSL5 promoter not shown by ChIP","Relative importance of these regulators across tissues not established","Whether these inputs converge on the same or different ACSL5 isoforms is unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for ACSL5's substrate selectivity and mitochondrial targeting; the identity of the E3 ubiquitin ligase(s) that mark ACSL5 for K48-linked degradation; the specific acyl-CoA or lipid species mediating ACSL5's effects on MHC-I presentation, ferroptosis, and senescence; whether ACSL5 has non-catalytic scaffolding functions (e.g., MDM2 stabilization); and whether pharmacological ACSL5 modulation can safely replicate the anorexigenic or immunomodulatory effects observed in animal models.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or cryo-EM model of ACSL5","E3 ligase targeting ACSL5 for ubiquitination not identified","No selective pharmacological inhibitor or activator reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,7,15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,5,11,12,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,20]}],"complexes":[],"partners":["SIRT6","USP29","OTUB1","MDM2","MIB1","HSPA9"],"other_free_text":[]},"mechanistic_narrative":"ACSL5 is a mitochondria-associated long-chain acyl-CoA synthetase that activates C10–C18 fatty acids—with preference for C16–C18 unsaturated species—to their CoA thioesters, channeling them predominantly toward β-oxidation and thereby governing cellular energy metabolism, lipid homeostasis, and fat absorption [PMID:9722683, PMID:17761945, PMID:26977393]. In the intestine, ACSL5 is the dominant ACSL isoform; its loss reduces dietary fat absorption, increases distal intestinal fatty acid delivery to enteroendocrine cells, and elevates GLP-1/PYY secretion to suppress food intake, protecting against diet-induced obesity [PMID:26977393, PMID:38499083, PMID:33106515]. ACSL5 activity is regulated post-translationally by SIRT6-mediated deacetylation (enhancing activity) and by USP29- and OTUB1-mediated K48-linked deubiquitination that prevents proteasomal degradation, and transcriptionally by ERK/oncostatin M, STAT3, OC2/ONECUT2, IRF-1, and the JAB1–CRL4B repressor complex [PMID:36208627, PMID:39355870, PMID:40280245, PMID:17761945, PMID:39557186, PMID:32129880, PMID:41388188]. In cancer, ACSL5 modulates MHC-I antigen presentation to sensitize tumors to immune checkpoint blockade, promotes cellular senescence through acetyl-CoA-driven 53BP1 acetylation, confers ferroptosis resistance, and facilitates metastatic adaptation via COX2/PGE2 signaling [PMID:38350448, PMID:40595416, PMID:39927464, PMID:41570334]."},"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 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saturated fatty acids (C10–C18) and shows a distinct preference for C16–C18 unsaturated fatty acids (oleate, arachidonate, EPA, DHA) compared to ACS1/ACS2, as demonstrated by purification from E. coli and enzymatic characterization.\",\n      \"method\": \"Recombinant protein overexpression in E. coli, purification to homogeneity, enzymatic activity assay with various fatty acid substrates\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic reconstitution with purified recombinant protein and substrate profiling\",\n      \"pmids\": [\"9722683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Oncostatin M (OM) activates transcription of ACSL5 (and ACSL3) in hepatocytes through the ERK signaling pathway, and overexpression of ACSL5 alone partitions fatty acids into β-oxidation, reducing triglyceride accumulation; siRNA knockdown of ACSL5 abrogates OM-enhanced fatty acid oxidation.\",\n      \"method\": \"Transcriptional reporter assays, siRNA knockdown, overexpression in HepG2 cells, fatty acid oxidation assays, in vivo hamster model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (OE, KD, in vivo) establishing ACSL5's role in fatty acid β-oxidation downstream of ERK signaling\",\n      \"pmids\": [\"17761945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Whole-body ACSL5 knockout mice show ~80% reduction in jejunal ACSL activity, reduced fat mass, increased energy expenditure, improved insulin sensitivity, delayed dietary triglyceride absorption after olive oil gavage, and markedly elevated hepatic and serum FGF21 levels (~16-fold and ~13-fold, respectively), establishing ACSL5 as a key regulator of intestinal fat absorption and whole-body energy metabolism.\",\n      \"method\": \"Conditional/whole-body knockout mouse model, indirect calorimetry, insulin tolerance test, oral fat gavage/triglyceride appearance assay, ACSL activity assays, FGF21 quantification\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined metabolic phenotypes and mechanistic readouts\",\n      \"pmids\": [\"26977393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The TCF7L2 type 2 diabetes risk variant rs7903146 resides in a regulatory element that physically contacts the ACSL5 promoter (demonstrated by 4C and Capture-C); CRISPR deletion of this region reduces ACSL5 mRNA up to 30-fold and abolishes chromatin contacts with the ACSL5 promoter, identifying ACSL5 as the gene under the influence of this diabetes-associated variant.\",\n      \"method\": \"CRISPR/Cas9 deletion, global gene expression analysis, circularized chromosome conformation capture (4C), Capture-C, Western blot\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR deletion plus chromatin conformation capture with multiple deletion sizes confirming result\",\n      \"pmids\": [\"27539148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The rs2419621 T allele of ACSL5 is associated with higher levels of the 683 aa ACSL5 protein isoform, which localizes predominantly to mitochondria (vs. the 739 aa isoform), and drives greater fatty acid oxidation in C2C12 myoblasts overexpressing human ACSL5, in primary rectus abdominis myotubes from T-allele carriers, and increased complex I/II respiration in vastus lateralis biopsies.\",\n      \"method\": \"14C palmitic acid oxidation, Western blot, subcellular localization by overexpression in C2C12 cells, high-resolution respirometry on muscle biopsies\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro, ex vivo, tissue) but single lab study with small sample sizes\",\n      \"pmids\": [\"29605434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT6 binds saturated fatty acids (especially palmitic acid), which triggers its nuclear export to the cytoplasm where it directly deacetylates ACSL5, enhancing ACSL5-mediated fatty acid β-oxidation; hepatic overexpression of a deacetylated ACSL5 mimic attenuates NAFLD in Sirt6 liver-specific knockout mice, and NASH tissues show reduced cytoplasmic SIRT6 and increased ACSL5 acetylation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, deacetylation assays, hepatic overexpression/depletion in mouse models, deacetylation-mimic rescue experiments, patient tissue analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical and in vivo methods with mechanistic rescue experiments in a single comprehensive study\",\n      \"pmids\": [\"36208627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated silencing of ACSL5 in Jurkat T cells decreases PMA/ionomycin-induced apoptosis to control levels and reduces mRNA expression of FAS, FASLG, and TNF, establishing a pro-apoptotic role for ACSL5 in T lymphocytes.\",\n      \"method\": \"siRNA knockdown, apoptosis assay, quantitative RT-PCR for apoptosis-related genes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined apoptotic phenotype and gene expression readouts, single lab\",\n      \"pmids\": [\"22163040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ACSL5 overexpression in CaCo2 cells induces ~2-fold increase of mortalin (HSPA9) specifically in mitochondria (not cytoplasm), mediated through disturbance of acyl-CoA/sphingolipid metabolism; this mitochondrial mortalin upregulation is dependent on wild-type TP53 status and is observed in normal intestinal mucosa with an increasing gradient from crypt to villus tip.\",\n      \"method\": \"Mitochondrial proteomics of ACSL5 transfectants vs. CaCo2 controls, Western blot, siRNA knockdown, tandem mass spectrometry lipid analysis, immunohistochemistry of normal mucosa and adenocarcinomas\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus multiple validation methods, but single lab\",\n      \"pmids\": [\"24770931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A functional variant rs2256368:A>G causes skipping of exon 20 in ACSL5 transcripts (ACSL5-Δ20) in ~20–40% of RNA molecules, as demonstrated by an exon-skipping assay; this splice variant is linked to the migraine-associated variant rs12355831, implicating altered mitochondrial long-chain fatty acid activation in migraine pathology.\",\n      \"method\": \"eQTL analysis of GEUVADIS RNA-seq data, exon-skipping assay with direct causality demonstration\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct exon-skipping assay demonstrates functional causality of the variant, but mechanistic downstream consequences are inferred\",\n      \"pmids\": [\"27189022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A 103.3 kb deletion encompassing the ACSL5 gene (and ZDHHC6) in Australian Kelpie dogs causes complete absence of ACSL5 expression in jejunal tissue and results in intestinal lipid malabsorption, steatorrhea, and stunted growth, establishing ACSL5 as essential for intestinal long-chain fatty acid absorption in vivo.\",\n      \"method\": \"Genome-wide association analysis, whole transcriptomic sequencing confirming absent ACSL5 expression, PCR-based diagnostic test, autosomal recessive inheritance confirmation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural loss-of-function model with transcriptomic confirmation and clear phenotypic readout\",\n      \"pmids\": [\"33106515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL5 regulates MHC-I-mediated antigen presentation; ACSL5 expression sensitizes tumors to PD-1 blockade and to CD8+ T cell cytotoxicity in vitro, and elaidic acid (a trans LCFA) phenocopies ACSL5 to enhance MHC-I expression and suppress tumor growth in vivo.\",\n      \"method\": \"In vivo PD-1 blockade tumor models, in vitro CD8+ T cell cytotoxicity assays, ACSL5 substrate screening, MHC-I expression assays, dietary supplementation experiments\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo orthogonal methods establishing ACSL5's mechanistic role in antigen presentation\",\n      \"pmids\": [\"38350448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP29 directly interacts with ACSL5 and stabilizes it by promoting K48-linked deubiquitination, thereby preventing proteasomal degradation of ACSL5; loss of USP29 reduces ACSL5 levels and fatty acid β-oxidation, exacerbating hepatic steatosis in MASLD, while the hepatoprotective effect of USP29 overexpression is dependent on ACSL5.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), USP29 KO and OE in mice and hepatocytes, rescue experiments with ACSL5\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding demonstrated by Co-IP, K48 deubiquitination mechanistically characterized, in vivo rescue experiment\",\n      \"pmids\": [\"39355870\"],\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 during high-fat feeding; loss of intestinal ACSL5 increases fatty acid content in the distal small intestine, elevates postprandial GLP-1 and PYY secretion, and GLP-1 receptor antagonism partially restores food intake, demonstrating that intestinal ACSL5 regulates energy balance via enteroendocrine signaling.\",\n      \"method\": \"Tamoxifen-inducible intestine-specific Cre knockout mouse model, metabolic phenotyping, GLP-1/PYY measurement after TAG challenge, GLP-1 receptor antagonist treatment, dietary fat absorption studies\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with mechanistic rescue (receptor antagonist), multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"38499083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAT3 transcriptionally activates ACSL5 under high glucose/palmitic acid conditions by binding the ACSL5 promoter; ACSL5 promotes lipid deposition and lipoapoptosis in proximal tubular epithelial cells, and concurrent STAT3 knockdown with ACSL5 overexpression mitigates lipoapoptosis compared to ACSL5 overexpression alone.\",\n      \"method\": \"ChEA3 database prediction, STAT3 knockdown with RT-qPCR, promoter activation assay, ACSL5 KD and OE in BUMPT cells with Oil Red O staining, FFA ELISA, Western blot, diabetic mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — promoter activation and rescue experiments, but single lab with partial mechanistic follow-up\",\n      \"pmids\": [\"39557186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUB1 directly interacts with ACSL5 (identified by mass spectrometry), deubiquitinates ACSL5, and promotes its stability; OTUB1 overexpression improves fatty acid oxidation and alleviates APAP-induced liver injury in vivo and in vitro, and this protective effect on FAO is abolished when ACSL5 is co-depleted.\",\n      \"method\": \"Mass spectrometry identification of ACSL5 as OTUB1 substrate, Co-IP, deubiquitination assay, OTUB1 OE/KD in mice and hepatocytes, ACSL5 rescue/co-depletion experiments\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — MS-based substrate identification, Co-IP, in vitro deubiquitination, in vivo rescue, single comprehensive study\",\n      \"pmids\": [\"40280245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSL5 promotes fatty acid oxidation in colorectal cancer cells, operates within a p53 regulatory loop (p53 transcriptionally upregulates ACSL5; ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53), relieves p53-mediated inhibition of PGAM1 to drive glycolysis, and its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle.\",\n      \"method\": \"ACSL5 KD/OE in colorectal cancer cells, metabolic flux assays (glycolysis, OXPHOS), Co-IP (ACSL5-MIB1-MDM2 competition), p53 transcriptional reporter assays, PGAM1 activity assay, ROS measurement, oxaliplatin sensitivity assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway placement experiments in a single study, but not yet independently replicated\",\n      \"pmids\": [\"41355704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSL5 promotes cellular senescence in bladder cancer by increasing acetyl-CoA production through fatty acid oxidation; elevated acetyl-CoA drives K1360 acetylation of 53BP1, enhancing recruitment of the p53-p21 senescent signaling axis to the nucleus; DNMT1-mediated CpG methylation silences ACSL5 in bladder cancer.\",\n      \"method\": \"ACSL5 OE/KD in bladder cancer cells, acetyl-CoA measurement, 53BP1 acetylation assay (K1360 site), p53-p21 pathway analysis, DNMT1 inhibition, in vitro and in vivo senescence assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway from ACSL5 → acetyl-CoA → 53BP1 acetylation → senescence established with multiple methods, single lab\",\n      \"pmids\": [\"40595416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAB1 forms a transcriptional repressor complex with CUL4B (CRL4B) that co-occupies the promoters of PPARG and ACSL5, leading to their transcriptional repression; JAB1 promotes breast cancer cell proliferation, invasion, and stemness by stabilizing CUL4B and suppressing ACSL5-mediated fatty acid metabolism.\",\n      \"method\": \"ChIP assay for CRL4B complex at PPARG/ACSL5 promoters, CUL4B stabilization assay, JAB1 OE/KD in breast cancer cells with proliferation/invasion/stemness readouts\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter co-occupancy, functional consequences validated, single lab\",\n      \"pmids\": [\"41388188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSL5 expression is induced in kidney tubular cells via IRF-1 signaling (part of a gamma interferon-related gene signature); ACSL5 maintains ATP production and cell viability and shapes the tubular cell lipidome by reducing ceramide accumulation and modulating glycerolipid content.\",\n      \"method\": \"Transcriptomic, metabolomic, and lipidomic analyses of experimental models and patient cohorts; IRF-1 signaling manipulation in kidney tubular cells; cell viability and ATP assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with experimental validation in tubular cells, single lab\",\n      \"pmids\": [\"40546938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AURKB inhibition in rhabdomyosarcoma reduces NPM1, which decreases SP1 transcription factor activity, leading to reduced ACSL5 expression; loss of ACSL5 promotes apoptosis and ferroptosis in RMS cells, establishing an AURKB/NPM1/SP1/ACSL5 axis in apoptosis/ferroptosis resistance.\",\n      \"method\": \"AURKB inhibitor treatment, NPM1/SP1/ACSL5 KD in RMS cells, apoptosis and ferroptosis assays in vitro, xenograft tumor growth assays in vivo\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established with sequential KD experiments and defined ferroptosis/apoptosis readouts, single lab\",\n      \"pmids\": [\"39927464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSL5 in lung-metastatic breast cancer cells facilitates adaptation to palmitic acid (PA) enriched in the pulmonary microenvironment by inducing COX2-mediated PGE2 accumulation and activating PI3K/AKT and ERK signaling through EP4; ACSL5 also boosts palmitoyltransferase levels to further enhance COX2 expression, and this axis can be blocked by the palmitoylation inhibitor 2-bromopalmitate.\",\n      \"method\": \"ACSL5 OE/KD in breast cancer cell lines, COX2/PGE2 measurement, EP4 signaling assays, palmitoyltransferase activity assays, 2-bromopalmitate inhibition, breast cancer mouse metastasis models, patient tumor analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway components validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"41570334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The ONECUT2 (OC2) transcription factor directly activates ACSL5 transcription in gastric cancer cells, as shown by ChIP-seq and RNA-seq; OC2 upregulation (driven by promoter hypomethylation) triggers ACSL5 expression in intestinal metaplasia and gastric cancer, and OC2 knockdown suppresses tumorigenesis in nude mice.\",\n      \"method\": \"ChIP-seq, RNA-seq, stable transfection/knockdown of OC2, bisulfite sequencing for methylation, xenograft tumorigenesis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq demonstrates direct transcriptional activation, functional KD in vivo, single lab\",\n      \"pmids\": [\"32129880\"],\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 to acyl-CoA thioesters, directing them toward β-oxidation and lipid metabolism; its activity and stability are regulated post-translationally by SIRT6-mediated deacetylation (enhancing activity), K48-linked ubiquitination/deubiquitination by USP29 and OTUB1, and transcriptionally by ERK/oncostatin M, STAT3, and OC2 signaling, while in the intestine ACSL5 is the dominant ACSL isoform controlling dietary fat absorption and enteroendocrine GLP-1/PYY secretion, and in cancer cells it modulates MHC-I antigen presentation, ferroptosis sensitivity, cellular senescence via acetyl-CoA/53BP1 acetylation, and metabolic adaptation to nutrient stress.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACSL5 is a mitochondria-associated long-chain acyl-CoA synthetase that activates C10–C18 fatty acids—with preference for C16–C18 unsaturated species—to their CoA thioesters, channeling them predominantly toward β-oxidation and thereby governing cellular energy metabolism, lipid homeostasis, and fat absorption [PMID:9722683, PMID:17761945, PMID:26977393]. In the intestine, ACSL5 is the dominant ACSL isoform; its loss reduces dietary fat absorption, increases distal intestinal fatty acid delivery to enteroendocrine cells, and elevates GLP-1/PYY secretion to suppress food intake, protecting against diet-induced obesity [PMID:26977393, PMID:38499083, PMID:33106515]. ACSL5 activity is regulated post-translationally by SIRT6-mediated deacetylation (enhancing activity) and by USP29- and OTUB1-mediated K48-linked deubiquitination that prevents proteasomal degradation, and transcriptionally by ERK/oncostatin M, STAT3, OC2/ONECUT2, IRF-1, and the JAB1–CRL4B repressor complex [PMID:36208627, PMID:39355870, PMID:40280245, PMID:17761945, PMID:39557186, PMID:32129880, PMID:41388188]. In cancer, ACSL5 modulates MHC-I antigen presentation to sensitize tumors to immune checkpoint blockade, promotes cellular senescence through acetyl-CoA-driven 53BP1 acetylation, confers ferroptosis resistance, and facilitates metastatic adaptation via COX2/PGE2 signaling [PMID:38350448, PMID:40595416, PMID:39927464, PMID:41570334].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the enzymatic identity of ACSL5: purified recombinant protein demonstrated it is a long-chain acyl-CoA synthetase with a distinct substrate profile (C10–C18, preferring C16–C18 unsaturated fatty acids), distinguishing it from other ACSL family members.\",\n      \"evidence\": \"Recombinant overexpression in E. coli, purification to homogeneity, enzymatic activity assays with diverse fatty acid substrates\",\n      \"pmids\": [\"9722683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No determination of subcellular localization\", \"No tissue expression data beyond initial cloning\", \"Kinetic parameters for all substrates not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking ACSL5 to fatty acid β-oxidation and transcriptional regulation: oncostatin M induces ACSL5 via ERK signaling in hepatocytes, and ACSL5 overexpression preferentially channels fatty acids into β-oxidation rather than triglyceride storage, a function abolished by siRNA knockdown.\",\n      \"evidence\": \"Transcriptional reporter assays, siRNA knockdown, overexpression in HepG2 cells, fatty acid oxidation assays, in vivo hamster model\",\n      \"pmids\": [\"17761945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ACSL5 preferentially directs acyl-CoA to β-oxidation versus other fates not defined\", \"ERK-responsive cis-regulatory element not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealing a pro-apoptotic role in lymphocytes: ACSL5 silencing reduced activation-induced apoptosis and downregulated FAS/FASLG/TNF expression in T cells, expanding ACSL5 function beyond metabolic channeling.\",\n      \"evidence\": \"siRNA knockdown in Jurkat T cells, apoptosis assays, RT-qPCR for death receptor ligands\",\n      \"pmids\": [\"22163040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking acyl-CoA production to death receptor gene transcription unknown\", \"Not confirmed in primary T cells\", \"No lipid metabolite analysis\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting ACSL5 to mitochondrial proteome remodeling: ACSL5 overexpression specifically upregulated mitochondrial mortalin (HSPA9) through altered acyl-CoA/sphingolipid metabolism in a p53-dependent manner, linking ACSL5 activity to mitochondrial stress responses.\",\n      \"evidence\": \"Mitochondrial proteomics, Western blot, siRNA knockdown, tandem mass spectrometry lipidomics in CaCo2 cells\",\n      \"pmids\": [\"24770931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism for sphingolipid-driven mortalin induction not established\", \"Single cell line\", \"Functional consequence of mortalin upregulation not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing ACSL5 as the dominant intestinal ACSL and a regulator of whole-body energy metabolism: ACSL5-knockout mice exhibited ~80% loss of jejunal ACSL activity, delayed fat absorption, reduced adiposity, improved insulin sensitivity, and massively elevated FGF21, while a linked genetic study demonstrated that a functional splice variant (exon 20 skipping) alters ACSL5 activity.\",\n      \"evidence\": \"Whole-body knockout mouse with indirect calorimetry, oral fat gavage, insulin tolerance tests, FGF21 quantification; eQTL and exon-skipping assay for splice variant\",\n      \"pmids\": [\"26977393\", \"27189022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the metabolic phenotype is entirely intestine-autonomous was not resolved (whole-body KO)\", \"Direct substrates and acyl-CoA species altered in intestinal epithelium not profiled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking the TCF7L2 type 2 diabetes risk locus to ACSL5 regulation: CRISPR deletion of the rs7903146-containing regulatory element reduced ACSL5 mRNA up to 30-fold and abolished chromatin contacts with the ACSL5 promoter, establishing ACSL5 as a target gene of this diabetes-associated variant.\",\n      \"evidence\": \"CRISPR/Cas9 deletion, 4C and Capture-C chromatin conformation capture, gene expression profiling\",\n      \"pmids\": [\"27539148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of reduced ACSL5 in the cell types relevant to diabetes (β-cells, intestine) not tested\", \"Whether ACSL5 reduction mediates the diabetes risk phenotype not proven\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating isoform-specific localization and function: the shorter 683 aa ACSL5 isoform (favored by the rs2419621 T allele) preferentially localizes to mitochondria and drives greater fatty acid oxidation and mitochondrial respiration compared to the longer isoform.\",\n      \"evidence\": \"14C palmitate oxidation in C2C12 myoblasts, subcellular localization, high-resolution respirometry on human muscle biopsies\",\n      \"pmids\": [\"29605434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for differential mitochondrial targeting of the two isoforms not defined\", \"Small human sample size\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirming ACSL5 is essential for intestinal fat absorption in a natural loss-of-function model: a homozygous deletion encompassing ACSL5 in dogs caused complete loss of jejunal ACSL5 expression, steatorrhea, and stunted growth, phenocopying the mouse knockout.\",\n      \"evidence\": \"GWAS, whole transcriptomic sequencing, autosomal recessive inheritance confirmation in Australian Kelpie dogs\",\n      \"pmids\": [\"33106515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Deletion also removes ZDHHC6, so contribution of ZDHHC6 loss to phenotype not excluded\", \"No biochemical characterization of residual ACSL activity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying a direct transcriptional activator in gastric tissue: ONECUT2 binds the ACSL5 promoter and activates its transcription, with OC2 promoter hypomethylation driving ACSL5 upregulation in intestinal metaplasia and gastric cancer.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, OC2 knockdown/overexpression, bisulfite sequencing, xenograft tumorigenesis\",\n      \"pmids\": [\"32129880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSL5 is the key downstream mediator of OC2 oncogenic effects not formally tested by ACSL5 rescue\", \"Mechanism linking ACSL5 to gastric tumorigenesis not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing a post-translational activation mechanism: SIRT6, triggered by palmitic acid binding, translocates to the cytoplasm and directly deacetylates ACSL5, enhancing its enzymatic activity; a deacetylation-mimic ACSL5 mutant rescues NAFLD in Sirt6-deficient livers.\",\n      \"evidence\": \"Co-immunoprecipitation, deacetylation assays, subcellular fractionation, hepatic overexpression/depletion in mice, deacetylation-mimic rescue, human NASH tissue analysis\",\n      \"pmids\": [\"36208627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific acetylation sites on ACSL5 targeted by SIRT6 not fully mapped\", \"Whether SIRT6-ACSL5 axis operates in non-hepatic tissues not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolving the intestine-autonomous mechanism: intestine-specific ACSL5 knockout protected mice from diet-induced obesity exclusively through reduced food intake; loss of ACSL5 increased distal intestinal fatty acid content, elevated postprandial GLP-1/PYY, and GLP-1 receptor antagonism partially reversed the anorectic phenotype.\",\n      \"evidence\": \"Tamoxifen-inducible intestine-specific Cre knockout, metabolic phenotyping, GLP-1/PYY measurement, GLP-1R antagonist rescue\",\n      \"pmids\": [\"38499083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How unesterified fatty acids reaching the distal intestine stimulate enteroendocrine cells not molecularly defined\", \"Whether ACSL5 inhibition in humans would recapitulate anorexigenic effects unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanding ACSL5 into cancer immunology: ACSL5 enhances MHC-I antigen presentation, sensitizing tumors to PD-1 blockade and CD8+ T cell killing; the trans fatty acid elaidic acid phenocopies ACSL5 to boost MHC-I expression and suppress tumor growth in vivo.\",\n      \"evidence\": \"In vivo tumor models with PD-1 blockade, CD8+ T cell cytotoxicity assays, ACSL5 substrate screening, dietary elaidic acid supplementation\",\n      \"pmids\": [\"38350448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid species mediating MHC-I upregulation not identified\", \"Whether effect generalizes across tumor types not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining a ubiquitin-mediated stability control mechanism: USP29 directly binds and deubiquitinates ACSL5 via K48-linked chains, preventing proteasomal degradation; loss of USP29 reduces ACSL5 levels and β-oxidation, worsening hepatic steatosis, while USP29 overexpression is hepatoprotective in an ACSL5-dependent manner.\",\n      \"evidence\": \"Co-immunoprecipitation, K48-linkage-specific ubiquitination assays, USP29 KO and OE in mice and hepatocytes, ACSL5 rescue experiments\",\n      \"pmids\": [\"39355870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitin sites on ACSL5 not mapped\", \"E3 ligase responsible for K48 ubiquitination of ACSL5 not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A second deubiquitinase (OTUB1) was identified as a direct ACSL5 stabilizer by mass spectrometry, paralleling USP29; OTUB1-mediated ACSL5 stabilization improves fatty acid oxidation and protects against APAP-induced liver injury in an ACSL5-dependent manner.\",\n      \"evidence\": \"Mass spectrometry substrate identification, Co-IP, deubiquitination assay, OTUB1 OE/KD in mice and hepatocytes, ACSL5 co-depletion rescue\",\n      \"pmids\": [\"40280245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP29 and OTUB1 act redundantly or in different contexts not resolved\", \"Structural basis of OTUB1–ACSL5 interaction unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In cancer, ACSL5 operates at a metabolic–signaling nexus: it promotes senescence in bladder cancer by generating acetyl-CoA that acetylates 53BP1-K1360 to activate the p53–p21 axis; in colorectal cancer it stabilizes MDM2 by competing with MIB1, suppressing p53, and activates glycolysis (PGAM1) and TCA cycle (IDH2); in rhabdomyosarcoma it confers ferroptosis resistance downstream of AURKB/NPM1/SP1; and in metastatic breast cancer it fuels COX2/PGE2 signaling via palmitoylation to activate PI3K/AKT and ERK through EP4.\",\n      \"evidence\": \"ACSL5 OE/KD across bladder, colorectal, rhabdomyosarcoma, and breast cancer cell lines; acetyl-CoA and 53BP1 acetylation assays; Co-IP for MIB1–MDM2 competition; ferroptosis and apoptosis assays; COX2/PGE2 measurement; in vivo xenograft and metastasis models\",\n      \"pmids\": [\"40595416\", \"41355704\", \"39927464\", \"41570334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many cancer-specific mechanisms reported by single labs and not yet independently replicated\", \"Whether these diverse downstream effects all stem from acyl-CoA channeling or involve non-catalytic ACSL5 functions is unclear\", \"Context-dependent tumor-suppressive versus oncogenic roles not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Additional transcriptional regulators of ACSL5 identified: STAT3 activates ACSL5 under diabetic conditions to promote lipoapoptosis in kidney tubular cells; JAB1–CRL4B represses ACSL5 at its promoter in breast cancer to suppress fatty acid metabolism; IRF-1 induces ACSL5 in kidney tubular cells to maintain ATP production and modulate the lipidome.\",\n      \"evidence\": \"ChIP for CRL4B at ACSL5 promoter; STAT3 promoter activation assay and KD/OE rescue in kidney cells; transcriptomic/lipidomic analysis with IRF-1 manipulation\",\n      \"pmids\": [\"39557186\", \"41388188\", \"40546938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3 binding to ACSL5 promoter not shown by ChIP\", \"Relative importance of these regulators across tissues not established\", \"Whether these inputs converge on the same or different ACSL5 isoforms is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for ACSL5's substrate selectivity and mitochondrial targeting; the identity of the E3 ubiquitin ligase(s) that mark ACSL5 for K48-linked degradation; the specific acyl-CoA or lipid species mediating ACSL5's effects on MHC-I presentation, ferroptosis, and senescence; whether ACSL5 has non-catalytic scaffolding functions (e.g., MDM2 stabilization); and whether pharmacological ACSL5 modulation can safely replicate the anorexigenic or immunomodulatory effects observed in animal models.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure or cryo-EM model of ACSL5\", \"E3 ligase targeting ACSL5 for ubiquitination not identified\", \"No selective pharmacological inhibitor or activator reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 7, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 5, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SIRT6\",\n      \"USP29\",\n      \"OTUB1\",\n      \"MDM2\",\n      \"MIB1\",\n      \"HSPA9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}