{"gene":"ACSL1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1996,"finding":"Rat ACSL1 (ACS1) purified from E. coli expression system demonstrated long-chain acyl-CoA synthetase activity with highest efficiency for saturated fatty acids with 10–18 carbons and unsaturated fatty acids including palmitoleate, oleate, and linoleate; deletion mutagenesis showed all five structural regions are required for enzymatic activity.","method":"Recombinant protein expression in E. coli, enzymatic activity assay, deletion mutagenesis","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified enzyme, mutagenesis of all five domains","pmids":["8973631"],"is_preprint":false},{"year":2000,"finding":"Purified rat recombinant ACSL1 (ACS1) efficiently catalyzes thioesterification of 2-arylpropionic acid NSAIDs (ibuprofen, fenoprofen) with marked stereoselectivity for the (-)R-enantiomer, identifying ACSL1 as the major enzyme responsible for the first step of chiral inversion of these drugs.","method":"Recombinant protein purification from E. coli, in vitro enzymatic activity assay with Michaelis-Menten kinetics, stereoselectivity measurement","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified enzyme, quantitative kinetic parameters measured","pmids":["10725307"],"is_preprint":false},{"year":2010,"finding":"ACSL1 and FATP1 are required for AMPK activation by adiponectin and insulin in mouse adipocytes; knockdown of either enzyme abolished the AMP/ATP ratio increase and AMPK activation, as well as stimulation of long-chain fatty acid uptake.","method":"siRNA knockdown in adipocytes, AMP/ATP ratio measurement, AMPK phosphorylation assay, fatty acid uptake assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, multiple orthogonal readouts","pmids":["20667975"],"is_preprint":false},{"year":2011,"finding":"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in 3T3-L1 adipocytes and increases acyl-CoA synthetase activity and fatty acid uptake indirectly via metabolic trapping rather than direct plasma membrane transport.","method":"Retroviral transduction for stable overexpression, confocal microscopy, subcellular fractionation, acyl-CoA synthetase activity assay, fatty acid uptake assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function with orthogonal localization and functional methods","pmids":["23024797"],"is_preprint":false},{"year":2011,"finding":"Overexpression of ACSL1 in human hepatoma cells (HuH7 and HepG2) localizes to mitochondria and significantly increases acyl-CoA synthetase activity and fatty acid uptake, supporting an indirect mechanism via esterification.","method":"Overexpression in HuH7/HepG2 cells, immunofluorescence co-localization, ACS activity assay, [3H]-oleic acid and fluorescent fatty acid uptake assay, quantitative FACS","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, single lab","pmids":["22022213"],"is_preprint":false},{"year":2020,"finding":"TBK1 functions as a scaffolding protein (in its inactive, unphosphorylated state during fasting) to localize ACSL1 to mitochondria, channeling acyl-CoAs toward β-oxidation; loss of TBK1 shifts ACSL1 to the endoplasmic reticulum, promoting fatty acid re-esterification and hepatic lipid accumulation.","method":"Liver-specific TBK1 knockout mice, subcellular fractionation, fatty acid oxidation assay, rescue with kinase-dead TBK1 expression, Co-immunoprecipitation","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined metabolic phenotype, rescue experiment, multiple orthogonal methods","pmids":["33152322"],"is_preprint":false},{"year":2021,"finding":"ACSL1 mediates ferroptosis triggered by conjugated linoleates (e.g., α-eleostearic acid) by promoting their incorporation into neutral lipids including triacylglycerols; interfering with triacylglycerol biosynthesis suppresses αESA-triggered ferroptosis but not GPX4-inhibition-triggered ferroptosis.","method":"Genetic manipulation (knockdown/overexpression), lipidomics, lipid peroxidation assay, cell death assay, pharmacological inhibition of triacylglycerol biosynthesis, in vivo tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic and biochemical methods, in vivo validation","pmids":["33854057"],"is_preprint":false},{"year":2021,"finding":"ACSL1 N-terminal 100 amino acids are essential for mitochondrial outer membrane localization via interaction with CPT1b; ACSL1 wild type but not N-terminal deletion mutant increases fatty acid oxidation and ameliorates palmitate-induced insulin resistance in C2C12 myotubes.","method":"Deletion mutagenesis of N-terminal 100 aa, subcellular localization by microscopy, Co-immunoprecipitation with CPT1b, fatty acid oxidation assay, insulin resistance assay","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with interaction assay and functional readout","pmids":["34511469"],"is_preprint":false},{"year":2021,"finding":"Acsl1 knockout in mice causes severe skin barrier defects and embryonic lethality due to failure to activate linoleic acid, resulting in reduced ω-O-acylceramide (Cer[EOS]) synthesis and accumulation of the precursor ω-hydroxy ceramide (Cer[OS]).","method":"Acsl1 knockout mouse model, lipidomics/ceramide profiling, gene expression analysis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined biochemical and lethal phenotype, lipidomic mechanistic validation","pmids":["34813948"],"is_preprint":false},{"year":2023,"finding":"ACSL1 increases N-myristoylation of ferroptosis suppressor protein 1 (FSP1), inhibiting FSP1 degradation and promoting its translocation to the cell membrane, thereby counteracting oxidative stress-induced ferroptosis in ovarian cancer cells.","method":"Genetic manipulation (ACSL1 overexpression/knockdown), N-myristoylation assay, FSP1 protein stability assay, membrane fractionation, lipid peroxidation assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular biology methods, single lab","pmids":["36882396"],"is_preprint":false},{"year":2020,"finding":"ACSL1 activates the AMPK and Src pathways via protein myristoylation in ovarian cancer cells, converting NM cells to an HM phenotype with enhanced fatty acid beta-oxidation and increased metastasis.","method":"Shotgun proteomics, ACSL1 overexpression in NM cells, AMPK/Src pathway activation assays, lipidomics","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic + functional validation, single lab","pmids":["33082557"],"is_preprint":false},{"year":2016,"finding":"SREBP2 specifically activates a C-promoter-derived ACSL1 transcript via a sterol regulatory element (SRE) motif in the ACSL1 C-promoter; demonstrated by promoter activity assay, DNA binding assay, and SREBP2 knockdown reducing ACSL1 mRNA and protein.","method":"Promoter activity assay, EMSA/DNA binding assay, SREBP2 knockdown in HepG2, in vivo hamster/mouse models with statin or high cholesterol/fat diet","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — promoter mutagenesis, DNA binding, KD and in vivo validation","pmids":["26728456"],"is_preprint":false},{"year":2018,"finding":"Hepatic ACSL1 depletion leads to dysregulated cholesterol metabolism (hypercholesterolemia, reduced LDL receptor) and repression of bile acid biosynthetic enzyme expression; FXR activation by obeticholic acid represses ACSL1 in an FXR-dependent manner, identifying ACSL1 as a novel FXR target gene.","method":"Adenoviral shRNA-mediated hepatic ACSL1 knockdown in mice, genome-wide gene expression profiling, FXR KO mice with FXR agonist treatment","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 — in vivo KD with genome-wide profiling, KO validation of regulatory mechanism","pmids":["30580099"],"is_preprint":false},{"year":2019,"finding":"TNFα-induced pro-inflammatory polarization of monocytes (upregulation of CD16, CD11b, CD11c, HLA-DR, IL-1β, MCP-1) requires ACSL1 and is mediated through NF-κB; ACSL1 inhibition (triacsin C) or siRNA knockdown significantly suppresses these effects, while β-oxidation and ceramide biosynthesis inhibition do not.","method":"ACSL1 inhibitor (triacsin C), siRNA knockdown, flow cytometry, ELISA, NF-κB reporter cells, Western blot for NF-κB phosphorylation","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic inhibition with defined mechanistic pathway, single lab","pmids":["30845379"],"is_preprint":false},{"year":2022,"finding":"TNFα-induced MMP-9 expression in monocytic cells is mediated through ACSL1, which activates the JNK/ERK/NF-κB axis; ACSL1 inhibition or knockdown reduces TNFα-induced phosphorylation of JNK, c-Jun, ERK1/2, and NF-κB p65 and NF-κB/AP-1 activity.","method":"ACSL1 inhibitor (triacsin C), siRNA knockdown, Western blot for pathway phosphorylation, NF-κB/AP-1 reporter cells, ELISA, qRT-PCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological inhibition with signaling pathway readouts, single lab","pmids":["37658104"],"is_preprint":false},{"year":2022,"finding":"Transcription factor CHREBP regulates ACSL1 mRNA expression in macrophages under high glucose conditions, and NF-κB (p65/RELA) drives ACSL1 mRNA upregulation in response to LPS; both transcription factors bind and activate the Acsl1 promoter at conserved sites.","method":"ACSL1 reporter gene assay, ChIP assay, CHREBP/p65 overexpression, bone marrow-derived macrophages from CHREBP KO mice, primary human monocytes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 — promoter reporter, ChIP, and KO macrophages with multiple orthogonal methods","pmids":["36054206"],"is_preprint":false},{"year":2024,"finding":"MCL-1 binds ACSL1 through a non-conventional BH3-domain interaction with the BH3-binding hydrophobic groove of MCL-1; genetic loss of Mcl1, mutagenesis, or BH3-mimetic MCL-1 inhibitors repress long-chain (but not short-chain) fatty acid β-oxidation in cells and in mouse livers and hearts.","method":"Co-immunoprecipitation, mutagenesis of BH3 domain, Mcl1 genetic knockout, BH3-mimetic inhibitor treatment, fatty acid oxidation assay in cells and tissues","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal co-IP, mutagenesis, KO, and in vivo functional validation","pmids":["38503284"],"is_preprint":false},{"year":2024,"finding":"Sortilin (encoded by Sort1) facilitates translocation of ACSL1 from mitochondria to the endolysosomal pathway for degradation in adipocytes; sortilin depletion increases mitochondrial ACSL1, activates AMPK/PGC1α signaling, and promotes beige fat activation and fatty acid oxidation.","method":"Sortilin KO in adipocytes, ACSL1 subcellular fractionation, AMPK/PGC1α signaling assays, thermogenic gene expression, HFD mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO with defined molecular mechanism and in vivo metabolic phenotype","pmids":["39232011"],"is_preprint":false},{"year":2023,"finding":"PRMT1 inhibition (GSK3368715) or PRMT1 knockout upregulates ACSL1 in AML cells by reducing H4R3me2a histone methylation at the ACSL1 promoter, thereby promoting ferroptosis; ACSL1 knockout reverses the ferroptosis sensitivity.","method":"PRMT1 KO, GSK3368715 treatment, ChIP for H4R3me2a at ACSL1 promoter, ACSL1 KO epistasis, lipid peroxidation assay, in vivo xenograft","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — ChIP, epistasis KO, in vivo validation, multiple orthogonal methods","pmids":["37144835"],"is_preprint":false},{"year":2024,"finding":"PRMT6 interacts with STAT1 to jointly repress ACSL1 transcription; PRMT6 reduction upregulates ACSL1, increases phospholipid-PUFA production, and drives ferroptosis in diabetic nephropathy; STAT1-specific inhibitor fludarabine reduces ACSL1 expression and delays DN progression.","method":"PRMT6 KO mice, transcriptomic and lipidomic analyses, molecular biology assays for PRMT6-STAT1 interaction and ACSL1 transcription, STAT1 inhibitor treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse, transcriptomic/lipidomic validation, mechanistic pathway analysis, single lab","pmids":["39134684"],"is_preprint":false},{"year":2025,"finding":"Ergosterol directly binds to the C-terminal acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1, stabilizing its closed conformation and allosterically activating its activity; ergosterol is enriched in mitochondria and promotes fatty acid β-oxidation specifically through ACSL1.","method":"In vitro binding assay, conformational analysis, structure-activity relationship analysis, ACSL1 KD/KO validation, mitochondrial fractionation, β-oxidation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct binding and structural analysis with functional validation, single lab","pmids":["39799570"],"is_preprint":false},{"year":2023,"finding":"ACSL1 inhibition or knockdown in macrophages suppresses palmitate-induced foamy/inflammatory phenotype by inhibiting the CD36-FABP4-p38-PPARδ signaling axis; in vivo oral administration of ACSL1 inhibitor triacsin-C in mice before acute high-fat feeding normalized inflammatory/foamy phenotype of circulating monocytes by suppressing FABP4 expression.","method":"ACSL1 pharmacological inhibition (triacsin C), siRNA knockdown, signaling pathway analysis, in vivo mouse model with oral triacsin C","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological inhibition with defined signaling pathway, in vivo validation","pmids":["37416456"],"is_preprint":false},{"year":1992,"finding":"The human gene FACL1 (ACSL1, encoding palmitoyl-CoA ligase) was chromosomally mapped to chromosome region 3q13 by in situ hybridization.","method":"In situ hybridization","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal localization by in situ hybridization","pmids":["1531127"],"is_preprint":false},{"year":2023,"finding":"FATP2 physically interacts with ACSL1 in NSCLC cells (shown by Co-IP); FATP2 silencing combined with ACSL1 overexpression further inhibits proliferation and lipid deposition and promotes fatty acid decomposition, indicating FATP2 regulates lipid metabolism through ACSL1.","method":"Co-immunoprecipitation, siRNA knockdown, ACSL1 overexpression (pcDNA-ACSL1), cell proliferation and lipid accumulation assays","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP, single lab, partial mechanistic follow-up","pmids":["37172427"],"is_preprint":false},{"year":2024,"finding":"PRMT7 catalyzes monomethylation of H4R3 (H4R3me1) at the HMGB2 promoter, enhancing HMGB2 transcription; HMGB2 then binds the ACSL1 promoter and activates ACSL1 transcription, driving ferroptosis in severe acute pancreatitis.","method":"PRMT7 overexpression/inhibition, ChIP for H4R3me1, HMGB2-ACSL1 promoter binding assay, ferroptosis assays in AR42J cells and SAP mouse model","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, promoter binding, epistasis validated in cells and in vivo mouse model","pmids":["38376246"],"is_preprint":false},{"year":2017,"finding":"NF-κB directly regulates ACSL1 transcription in liver cancer cells; the oncoprotein HBXIP acts as a coactivator with transcription factor Sp1 by binding the ACSL1 promoter to upregulate ACSL1 mRNA and protein in breast cancer cells.","method":"ChIP assay for HBXIP/Sp1 at ACSL1 promoter, HBXIP overexpression/knockdown, NF-κB inhibitor (PDTC), lipid droplet and triglyceride quantification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP assay identifying transcriptional mechanism, multiple labs reporting NF-κB regulation","pmids":["28132807","28359761"],"is_preprint":false},{"year":2022,"finding":"ACSL1 overexpression in K562 CML cells induces cellular senescence and inhibits cell growth via the SIRT1/p53/p21 axis; ACSL1 knockdown reverses imatinib-induced senescence.","method":"ACSL1 overexpression/knockdown, cell cycle analysis, senescence assays, Western blot for SIRT1/p53/p21 pathway, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss of function with pathway identification, in vivo validation","pmids":["36289272"],"is_preprint":false},{"year":2022,"finding":"ACSL1 knockdown in mice (via AAV9) promotes cardiomyocyte cell cycle progression from G0 to G2, enhances myocardial regeneration, and correlates with AKT activation and FOXO1 nuclear exclusion.","method":"AAV9-mediated ACSL1 knockdown in mice, RNA-seq of mouse hearts at different developmental ages, cell cycle analysis, AKT/FOXO1 signaling assays, myocardial infarction model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD with mechanistic pathway analysis, single lab","pmids":["35122795"],"is_preprint":false}],"current_model":"ACSL1 is a long-chain acyl-CoA synthetase that activates long-chain fatty acids to acyl-CoA thioesters at mitochondrial outer membranes (via N-terminal interaction with CPT1), directing substrates into β-oxidation; its subcellular localization is dynamically regulated (by TBK1 scaffolding and sortilin-mediated lysosomal trafficking), and it participates in diverse cellular processes including ferroptosis (by incorporating PUFAs into triacylglycerols and modulating FSP1 myristoylation), inflammatory signaling (via NF-κB/JNK/ERK cascades downstream of TNFα), skin barrier formation (via linoleic acid activation for ω-O-acylceramide synthesis), and transcriptional regulation by SREBP2, NF-κB, CHREBP, and FXR, while also being stabilized by direct binding to the BH3-binding groove of MCL-1."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that ACSL1 is a bona fide long-chain acyl-CoA synthetase with defined substrate specificity resolved the enzyme's catalytic identity and showed that all five structural regions are required for activity.","evidence":"Recombinant rat ACSL1 purified from E. coli, enzymatic activity assays and deletion mutagenesis","pmids":["8973631"],"confidence":"High","gaps":["No crystal structure available","Catalytic mechanism at atomic level unresolved","Isoform-specific substrate channeling not tested"]},{"year":2000,"claim":"Demonstrating that ACSL1 catalyzes stereoselective thioesterification of NSAID 2-arylpropionic acids expanded the enzyme's known substrate repertoire beyond endogenous fatty acids to xenobiotic metabolism.","evidence":"Purified recombinant ACSL1 kinetic assays with ibuprofen/fenoprofen enantiomers in vitro","pmids":["10725307"],"confidence":"High","gaps":["In vivo relevance for NSAID chiral inversion not confirmed","Structural basis for stereoselectivity unknown"]},{"year":2010,"claim":"Showing that ACSL1 is required for adiponectin/insulin-stimulated AMPK activation in adipocytes linked acyl-CoA synthetase activity to energy-sensing signaling, not just metabolic flux.","evidence":"siRNA knockdown in mouse adipocytes with AMP/ATP ratio, AMPK phosphorylation, and fatty acid uptake readouts","pmids":["20667975"],"confidence":"High","gaps":["Whether ACSL1 directly generates AMP or acts indirectly via acyl-CoA consumption unresolved","Contribution relative to FATP1 not fully delineated"]},{"year":2011,"claim":"Resolving that ACSL1 localizes to mitochondria (not the plasma membrane) and drives fatty acid uptake via metabolic trapping clarified that ACSL1 promotes uptake indirectly rather than functioning as a transporter.","evidence":"Stable overexpression in 3T3-L1 adipocytes and hepatoma cells with confocal microscopy, subcellular fractionation, and uptake assays","pmids":["23024797","22022213"],"confidence":"High","gaps":["Mechanism of metabolic trapping at molecular detail unclear","Whether ACSL1 also transiently localizes to other compartments not excluded"]},{"year":2016,"claim":"Identifying SREBP2-dependent transcriptional activation of ACSL1 via a sterol regulatory element in its C-promoter revealed how cholesterol homeostasis programs coordinate fatty acid activation.","evidence":"Promoter mutagenesis, EMSA, SREBP2 knockdown in HepG2, and in vivo statin/diet models in hamsters and mice","pmids":["26728456"],"confidence":"High","gaps":["Functional significance of alternative ACSL1 promoter usage not fully characterized","SREBP1 vs SREBP2 selectivity mechanism unknown"]},{"year":2018,"claim":"Demonstrating that hepatic ACSL1 depletion causes hypercholesterolemia and that FXR represses ACSL1 placed ACSL1 within the bile acid–cholesterol regulatory network.","evidence":"Adenoviral shRNA knockdown in mouse liver, genome-wide expression profiling, FXR KO mice with agonist treatment","pmids":["30580099"],"confidence":"High","gaps":["Whether ACSL1 regulation by FXR is direct or indirect not fully resolved","Downstream lipid species mediating cholesterol dysregulation not identified"]},{"year":2019,"claim":"Showing that ACSL1 is required for TNFα-induced NF-κB-dependent pro-inflammatory monocyte polarization established ACSL1 as a mediator of innate immune activation independent of β-oxidation.","evidence":"Triacsin C inhibition and siRNA knockdown in human monocytes with flow cytometry, ELISA, NF-κB reporter and phosphorylation assays","pmids":["30845379"],"confidence":"Medium","gaps":["Specific acyl-CoA species or lipid mediators linking ACSL1 to NF-κB activation not identified","Triacsin C inhibits multiple ACSLs, limiting isoform specificity"]},{"year":2020,"claim":"Discovering that TBK1 acts as a kinase-independent scaffold to retain ACSL1 at mitochondria during fasting, with loss shifting ACSL1 to the ER, established a regulated mechanism for partitioning fatty acids between oxidation and re-esterification.","evidence":"Liver-specific TBK1 KO mice, kinase-dead rescue, co-IP, subcellular fractionation, fatty acid oxidation assays","pmids":["33152322"],"confidence":"High","gaps":["Signal triggering TBK1-ACSL1 dissociation upon feeding not defined","Structural basis of TBK1–ACSL1 interaction unknown"]},{"year":2021,"claim":"Mapping the N-terminal 100 amino acids as necessary and sufficient for mitochondrial targeting via CPT1b interaction explained how ACSL1 couples fatty acid activation to the carnitine shuttle for β-oxidation.","evidence":"N-terminal deletion mutagenesis, co-IP with CPT1b, fatty acid oxidation and insulin resistance assays in C2C12 myotubes","pmids":["34511469"],"confidence":"High","gaps":["Whether TBK1 binding and CPT1b binding overlap or are sequential not tested","Whether all CPT1 isoforms interact equivalently unknown"]},{"year":2021,"claim":"Demonstrating that ACSL1 mediates ferroptosis by incorporating conjugated linoleates into triacylglycerols defined a TAG-dependent ferroptosis pathway distinct from GPX4-inhibitor-triggered cell death.","evidence":"Genetic manipulation, lipidomics, TAG biosynthesis inhibition, lipid peroxidation and cell death assays, in vivo tumor model","pmids":["33854057"],"confidence":"High","gaps":["How TAG-esterified PUFAs become peroxidized to execute ferroptosis not established","Relative contribution of ACSL1 vs other ACSL isoforms in different tissues unknown"]},{"year":2021,"claim":"Showing that Acsl1 knockout mice die with severe skin barrier defects from failed linoleic acid activation and ω-O-acylceramide synthesis revealed a non-redundant developmental role for ACSL1.","evidence":"Acsl1 whole-body KO mice, ceramide lipidomics, gene expression profiling","pmids":["34813948"],"confidence":"High","gaps":["Whether other ACSL isoforms partially compensate in heterozygotes not tested","Cell-type-specific requirements in epidermis not dissected"]},{"year":2022,"claim":"Identifying CHREBP and NF-κB (p65) as direct transcriptional activators of the Acsl1 promoter in macrophages linked glucose sensing and inflammatory signals to ACSL1 induction via conserved cis-elements.","evidence":"ChIP, promoter reporter assays, CHREBP overexpression and KO bone marrow-derived macrophages, primary human monocytes","pmids":["36054206"],"confidence":"High","gaps":["Interplay between CHREBP and NF-κB at the same promoter not resolved","Epigenetic regulation at these sites not explored"]},{"year":2023,"claim":"Demonstrating that ACSL1 promotes FSP1 N-myristoylation, stabilizing FSP1 and enabling its membrane translocation to suppress ferroptosis, revealed a second ferroptosis-related mechanism distinct from TAG incorporation.","evidence":"ACSL1 overexpression/knockdown, N-myristoylation and protein stability assays, membrane fractionation, lipid peroxidation assays in ovarian cancer cells","pmids":["36882396"],"confidence":"Medium","gaps":["Whether ACSL1 directly generates myristoyl-CoA for FSP1 modification or acts indirectly not shown","Generalizability beyond ovarian cancer cells untested"]},{"year":2023,"claim":"Showing that PRMT1 inhibition de-represses ACSL1 via reduced H4R3me2a at its promoter, driving ferroptosis in AML cells that is reversed by ACSL1 KO, placed ACSL1 as the effector of PRMT1-regulated ferroptosis.","evidence":"PRMT1 KO and inhibitor treatment, ChIP for H4R3me2a, ACSL1 KO epistasis, lipid peroxidation assay, in vivo xenograft","pmids":["37144835"],"confidence":"High","gaps":["Whether PRMT1 directly methylates H4R3 at the ACSL1 locus or acts through intermediary complexes not distinguished","Applicability beyond AML subtype not tested"]},{"year":2024,"claim":"Discovering that MCL-1 binds ACSL1 through its BH3-binding groove to stabilize the enzyme and sustain long-chain fatty acid oxidation linked anti-apoptotic BCL-2 family biology to metabolic regulation.","evidence":"Reciprocal co-IP, BH3-groove mutagenesis, Mcl1 KO, BH3-mimetic inhibitors, FAO assays in cells and mouse liver/heart","pmids":["38503284"],"confidence":"High","gaps":["Structural details of MCL-1–ACSL1 complex unresolved","Whether MCL-1 binding affects ACSL1 localization or only stability unknown"]},{"year":2024,"claim":"Identifying sortilin-mediated translocation of ACSL1 from mitochondria to endolysosomes for degradation revealed a regulated turnover mechanism that controls mitochondrial fatty acid oxidation and beige fat thermogenesis.","evidence":"Sortilin KO in adipocytes, ACSL1 subcellular fractionation, AMPK/PGC1α signaling, HFD mouse model","pmids":["39232011"],"confidence":"High","gaps":["Sorting signals on ACSL1 recognized by sortilin not mapped","Whether other ACSL isoforms are similarly regulated by sortilin unknown"]},{"year":2025,"claim":"Demonstrating that ergosterol directly binds the C-terminal ASLD1 domain of ACSL1 and allosterically stabilizes a closed, active conformation identified a sterol ligand that positively regulates enzymatic activity.","evidence":"In vitro binding assays, conformational analysis, structure-activity studies, ACSL1 KD/KO validation, β-oxidation assays","pmids":["39799570"],"confidence":"Medium","gaps":["Physiological relevance of ergosterol (a fungal sterol) to mammalian ACSL1 regulation unclear","Whether endogenous mammalian sterols act analogously not tested"]},{"year":null,"claim":"The specific acyl-CoA products that mediate ACSL1's activation of NF-κB/JNK signaling, the structural basis of the ACSL1–CPT1b and ACSL1–TBK1 complexes, and how TAG-incorporated PUFAs generated by ACSL1 are converted to lipid peroxides to execute ferroptosis remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian ACSL1 or its complexes","Lipid mediator identity downstream of ACSL1 in inflammatory signaling unknown","Mechanism linking ACSL1-generated TAG-PUFAs to ferroptotic peroxidation not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4,5,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5,7,8,12,16,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,9,18,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,14,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,13,14]}],"complexes":[],"partners":["CPT1B","TBK1","MCL1","SORT1","FSP1","FATP1","FATP2"],"other_free_text":[]},"mechanistic_narrative":"ACSL1 is a long-chain acyl-CoA synthetase that activates fatty acids (C10–C18 saturated and unsaturated) to their CoA thioesters, channeling lipid substrates into β-oxidation, membrane lipid remodeling, and signaling pathways [PMID:8973631, PMID:33152322]. ACSL1 localizes predominantly to the mitochondrial outer membrane via its N-terminal 100 amino acids through interaction with CPT1b, and this localization is dynamically regulated by TBK1 scaffolding (directing substrates toward β-oxidation) and sortilin-mediated endolysosomal trafficking for degradation [PMID:34511469, PMID:33152322, PMID:39232011]. ACSL1 participates in ferroptosis by incorporating polyunsaturated fatty acids into triacylglycerols and by promoting N-myristoylation and membrane targeting of FSP1, and it mediates TNFα-driven inflammatory signaling through the NF-κB/JNK/ERK cascade in monocytes [PMID:33854057, PMID:36882396, PMID:30845379, PMID:37658104]. Acsl1 knockout in mice causes lethal skin barrier defects due to failure of linoleic acid activation required for ω-O-acylceramide synthesis, and MCL-1 directly stabilizes ACSL1 through BH3-groove binding to sustain long-chain fatty acid oxidation in vivo [PMID:34813948, PMID:38503284]."},"prefetch_data":{"uniprot":{"accession":"P33121","full_name":"Long-chain-fatty-acid--CoA ligase 1","aliases":["Acyl-CoA synthetase 1","ACS1","Arachidonate--CoA ligase","Long-chain acyl-CoA synthetase 1","LACS 1","Long-chain acyl-CoA synthetase 2","LACS 2","Long-chain fatty acid-CoA ligase 2","Palmitoyl-CoA ligase 1","Palmitoyl-CoA ligase 2","Phytanate--CoA ligase"],"length_aa":698,"mass_kda":77.9,"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:21242590, PubMed:22633490, PubMed:24269233). Preferentially uses palmitoleate, oleate and linoleate (PubMed:24269233). Preferentially activates arachidonate than epoxyeicosatrienoic acids (EETs) or hydroxyeicosatrienoic acids (HETEs) (By similarity)","subcellular_location":"Mitochondrion outer membrane; Peroxisome membrane; Microsome membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P33121/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACSL1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACSL1","total_profiled":1310},"omim":[{"mim_id":"615591","title":"MACULAR DEGENERATION, AGE-RELATED, 15; ARMD15","url":"https://www.omim.org/entry/615591"},{"mim_id":"613825","title":"COMPLEMENT COMPONENT 9 DEFICIENCY; 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bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/14617640","citation_count":13,"is_preprint":false},{"pmid":"31052513","id":"PMC_31052513","title":"Ethylene Response of Plum ACC Synthase 1 (ACS1) Promoter is Mediated through the Binding Site of Abscisic Acid Insensitive 5 (ABI5).","date":"2019","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31052513","citation_count":13,"is_preprint":false},{"pmid":"10202812","id":"PMC_10202812","title":"Expression characteristics of CS-ACS1, CS-ACS2 and CS-ACS3, three members of the 1-aminocyclopropane-1-carboxylate synthase gene family in cucumber (Cucumis sativus L.) fruit under carbon dioxide stress.","date":"1999","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10202812","citation_count":13,"is_preprint":false},{"pmid":"31795267","id":"PMC_31795267","title":"The Molecular Characteristics of the FAM13A Gene and the Role of Transcription Factors ACSL1 and ASCL2 in Its Core Promoter Region.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/31795267","citation_count":13,"is_preprint":false},{"pmid":"36863716","id":"PMC_36863716","title":"ACSL1, CH25H, GPCPD1, and PLA2G12A as the potential lipid-related diagnostic biomarkers of acute myocardial infarction.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36863716","citation_count":12,"is_preprint":false},{"pmid":"37172427","id":"PMC_37172427","title":"FATP2 regulates non-small cell lung cancer by mediating lipid metabolism through ACSL1.","date":"2023","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/37172427","citation_count":12,"is_preprint":false},{"pmid":"35777132","id":"PMC_35777132","title":"CircPDHX promotes prostate cancer cell progression in vitro and tumor growth in vivo via miR-497-5p/ACSL1 axis.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35777132","citation_count":12,"is_preprint":false},{"pmid":"19816782","id":"PMC_19816782","title":"The 5' untranslated region of the VR-ACS1 mRNA acts as a strong translational enhancer in plants.","date":"2009","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/19816782","citation_count":12,"is_preprint":false},{"pmid":"39489819","id":"PMC_39489819","title":"ACSL1 improves pulmonary fibrosis by reducing mitochondrial damage and activating PINK1/Parkin mediated mitophagy.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39489819","citation_count":10,"is_preprint":false},{"pmid":"37509093","id":"PMC_37509093","title":"Transcriptional Regulation Associated with Subcutaneous Adipogenesis in Porcine ACSL1 Gene.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37509093","citation_count":10,"is_preprint":false},{"pmid":"36077572","id":"PMC_36077572","title":"Increased Lipids in Chlamydomonas reinhardtii by Multiple Regulations of DOF, LACS2, and CIS1.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077572","citation_count":10,"is_preprint":false},{"pmid":"35734439","id":"PMC_35734439","title":"Novel Insight Into the Role of ACSL1 Gene in Milk Production Traits in Buffalo.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35734439","citation_count":10,"is_preprint":false},{"pmid":"33287296","id":"PMC_33287296","title":"Polymorphisms of the ACSL1 Gene Influence Milk Production Traits and Somatic Cell Score in Chinese Holstein Cows.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/33287296","citation_count":10,"is_preprint":false},{"pmid":"34977220","id":"PMC_34977220","title":"Interference With ACSL1 Gene in Bovine Adipocytes: Transcriptome Profiling of mRNA and lncRNA Related to Unsaturated Fatty Acid Synthesis.","date":"2021","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/34977220","citation_count":9,"is_preprint":false},{"pmid":"40220428","id":"PMC_40220428","title":"Stevia rebaudiana root polysaccharide modulates liver metabolism, bile acid, and gut microbiota improving HFD-induced NAFLD: Potential roles of ACSL1 and FADS2.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40220428","citation_count":9,"is_preprint":false},{"pmid":"34601049","id":"PMC_34601049","title":"Interference with ACSL1 gene in bovine adipocytes: Transcriptome profiling of circRNA related to unsaturated fatty acid production.","date":"2021","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34601049","citation_count":9,"is_preprint":false},{"pmid":"30734982","id":"PMC_30734982","title":"The dependence of leaf senescence on the balance between 1-aminocyclopropane-1-carboxylate acid synthase 1 (ACS1)-catalysed ACC generation and nitric oxide-associated 1 (NOS1)-dependent NO accumulation in Arabidopsis.","date":"2019","source":"Plant biology (Stuttgart, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30734982","citation_count":9,"is_preprint":false},{"pmid":"22829935","id":"PMC_22829935","title":"Acyl coenzyme A synthetase long-chain 1 (ACSL1) gene polymorphism (rs6552828) and elite endurance athletic status: a replication study.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22829935","citation_count":9,"is_preprint":false},{"pmid":"16469493","id":"PMC_16469493","title":"Tissue-cell- and species-specific expression of gonadotropin-regulated long chain acyl-CoA synthetase (GR-LACS) in gonads, adrenal and brain. Identification of novel forms in the brain.","date":"2006","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16469493","citation_count":9,"is_preprint":false},{"pmid":"25999849","id":"PMC_25999849","title":"Exceptional longevity and muscle and fitness related genotypes: a functional in vitro analysis and case-control association replication study with SNPs THRH rs7832552, IL6 rs1800795, and ACSL1 rs6552828.","date":"2015","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25999849","citation_count":9,"is_preprint":false},{"pmid":"37239883","id":"PMC_37239883","title":"Genome-Wide Analysis and Functional Characterization of LACS Gene Family Associated with Lipid Synthesis in Cotton (Gossypium spp.).","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37239883","citation_count":8,"is_preprint":false},{"pmid":"37990603","id":"PMC_37990603","title":"Polystyrene microplastics interaction and influence on the growth kinetics and metabolism of tilapia gut probiotic Bacillus tropicus ACS1.","date":"2024","source":"Environmental science. 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Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/34813948","citation_count":8,"is_preprint":false},{"pmid":"36005135","id":"PMC_36005135","title":"Liraglutide Exerts Protective Effects by Downregulation of PPARγ, ACSL1 and SREBP-1c in Huh7 Cell Culture Models of Non-Alcoholic Steatosis and Drug-Induced Steatosis.","date":"2022","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36005135","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53430,"output_tokens":6445,"usd":0.128482},"stage2":{"model":"claude-opus-4-6","input_tokens":10205,"output_tokens":4080,"usd":0.229538},"total_usd":0.35802,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Rat ACSL1 (ACS1) purified from E. coli expression system demonstrated long-chain acyl-CoA synthetase activity with highest efficiency for saturated fatty acids with 10–18 carbons and unsaturated fatty acids including palmitoleate, oleate, and linoleate; deletion mutagenesis showed all five structural regions are required for enzymatic activity.\",\n      \"method\": \"Recombinant protein expression in E. coli, enzymatic activity assay, deletion mutagenesis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified enzyme, mutagenesis of all five domains\",\n      \"pmids\": [\"8973631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Purified rat recombinant ACSL1 (ACS1) efficiently catalyzes thioesterification of 2-arylpropionic acid NSAIDs (ibuprofen, fenoprofen) with marked stereoselectivity for the (-)R-enantiomer, identifying ACSL1 as the major enzyme responsible for the first step of chiral inversion of these drugs.\",\n      \"method\": \"Recombinant protein purification from E. coli, in vitro enzymatic activity assay with Michaelis-Menten kinetics, stereoselectivity measurement\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified enzyme, quantitative kinetic parameters measured\",\n      \"pmids\": [\"10725307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ACSL1 and FATP1 are required for AMPK activation by adiponectin and insulin in mouse adipocytes; knockdown of either enzyme abolished the AMP/ATP ratio increase and AMPK activation, as well as stimulation of long-chain fatty acid uptake.\",\n      \"method\": \"siRNA knockdown in adipocytes, AMP/ATP ratio measurement, AMPK phosphorylation assay, fatty acid uptake assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"20667975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in 3T3-L1 adipocytes and increases acyl-CoA synthetase activity and fatty acid uptake indirectly via metabolic trapping rather than direct plasma membrane transport.\",\n      \"method\": \"Retroviral transduction for stable overexpression, confocal microscopy, subcellular fractionation, acyl-CoA synthetase activity assay, fatty acid uptake assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with orthogonal localization and functional methods\",\n      \"pmids\": [\"23024797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of ACSL1 in human hepatoma cells (HuH7 and HepG2) localizes to mitochondria and significantly increases acyl-CoA synthetase activity and fatty acid uptake, supporting an indirect mechanism via esterification.\",\n      \"method\": \"Overexpression in HuH7/HepG2 cells, immunofluorescence co-localization, ACS activity assay, [3H]-oleic acid and fluorescent fatty acid uptake assay, quantitative FACS\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22022213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TBK1 functions as a scaffolding protein (in its inactive, unphosphorylated state during fasting) to localize ACSL1 to mitochondria, channeling acyl-CoAs toward β-oxidation; loss of TBK1 shifts ACSL1 to the endoplasmic reticulum, promoting fatty acid re-esterification and hepatic lipid accumulation.\",\n      \"method\": \"Liver-specific TBK1 knockout mice, subcellular fractionation, fatty acid oxidation assay, rescue with kinase-dead TBK1 expression, Co-immunoprecipitation\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined metabolic phenotype, rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"33152322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSL1 mediates ferroptosis triggered by conjugated linoleates (e.g., α-eleostearic acid) by promoting their incorporation into neutral lipids including triacylglycerols; interfering with triacylglycerol biosynthesis suppresses αESA-triggered ferroptosis but not GPX4-inhibition-triggered ferroptosis.\",\n      \"method\": \"Genetic manipulation (knockdown/overexpression), lipidomics, lipid peroxidation assay, cell death assay, pharmacological inhibition of triacylglycerol biosynthesis, in vivo tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and biochemical methods, in vivo validation\",\n      \"pmids\": [\"33854057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSL1 N-terminal 100 amino acids are essential for mitochondrial outer membrane localization via interaction with CPT1b; ACSL1 wild type but not N-terminal deletion mutant increases fatty acid oxidation and ameliorates palmitate-induced insulin resistance in C2C12 myotubes.\",\n      \"method\": \"Deletion mutagenesis of N-terminal 100 aa, subcellular localization by microscopy, Co-immunoprecipitation with CPT1b, fatty acid oxidation assay, insulin resistance assay\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with interaction assay and functional readout\",\n      \"pmids\": [\"34511469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Acsl1 knockout in mice causes severe skin barrier defects and embryonic lethality due to failure to activate linoleic acid, resulting in reduced ω-O-acylceramide (Cer[EOS]) synthesis and accumulation of the precursor ω-hydroxy ceramide (Cer[OS]).\",\n      \"method\": \"Acsl1 knockout mouse model, lipidomics/ceramide profiling, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined biochemical and lethal phenotype, lipidomic mechanistic validation\",\n      \"pmids\": [\"34813948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSL1 increases N-myristoylation of ferroptosis suppressor protein 1 (FSP1), inhibiting FSP1 degradation and promoting its translocation to the cell membrane, thereby counteracting oxidative stress-induced ferroptosis in ovarian cancer cells.\",\n      \"method\": \"Genetic manipulation (ACSL1 overexpression/knockdown), N-myristoylation assay, FSP1 protein stability assay, membrane fractionation, lipid peroxidation assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular biology methods, single lab\",\n      \"pmids\": [\"36882396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACSL1 activates the AMPK and Src pathways via protein myristoylation in ovarian cancer cells, converting NM cells to an HM phenotype with enhanced fatty acid beta-oxidation and increased metastasis.\",\n      \"method\": \"Shotgun proteomics, ACSL1 overexpression in NM cells, AMPK/Src pathway activation assays, lipidomics\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic + functional validation, single lab\",\n      \"pmids\": [\"33082557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SREBP2 specifically activates a C-promoter-derived ACSL1 transcript via a sterol regulatory element (SRE) motif in the ACSL1 C-promoter; demonstrated by promoter activity assay, DNA binding assay, and SREBP2 knockdown reducing ACSL1 mRNA and protein.\",\n      \"method\": \"Promoter activity assay, EMSA/DNA binding assay, SREBP2 knockdown in HepG2, in vivo hamster/mouse models with statin or high cholesterol/fat diet\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — promoter mutagenesis, DNA binding, KD and in vivo validation\",\n      \"pmids\": [\"26728456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatic ACSL1 depletion leads to dysregulated cholesterol metabolism (hypercholesterolemia, reduced LDL receptor) and repression of bile acid biosynthetic enzyme expression; FXR activation by obeticholic acid represses ACSL1 in an FXR-dependent manner, identifying ACSL1 as a novel FXR target gene.\",\n      \"method\": \"Adenoviral shRNA-mediated hepatic ACSL1 knockdown in mice, genome-wide gene expression profiling, FXR KO mice with FXR agonist treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with genome-wide profiling, KO validation of regulatory mechanism\",\n      \"pmids\": [\"30580099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNFα-induced pro-inflammatory polarization of monocytes (upregulation of CD16, CD11b, CD11c, HLA-DR, IL-1β, MCP-1) requires ACSL1 and is mediated through NF-κB; ACSL1 inhibition (triacsin C) or siRNA knockdown significantly suppresses these effects, while β-oxidation and ceramide biosynthesis inhibition do not.\",\n      \"method\": \"ACSL1 inhibitor (triacsin C), siRNA knockdown, flow cytometry, ELISA, NF-κB reporter cells, Western blot for NF-κB phosphorylation\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic inhibition with defined mechanistic pathway, single lab\",\n      \"pmids\": [\"30845379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNFα-induced MMP-9 expression in monocytic cells is mediated through ACSL1, which activates the JNK/ERK/NF-κB axis; ACSL1 inhibition or knockdown reduces TNFα-induced phosphorylation of JNK, c-Jun, ERK1/2, and NF-κB p65 and NF-κB/AP-1 activity.\",\n      \"method\": \"ACSL1 inhibitor (triacsin C), siRNA knockdown, Western blot for pathway phosphorylation, NF-κB/AP-1 reporter cells, ELISA, qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological inhibition with signaling pathway readouts, single lab\",\n      \"pmids\": [\"37658104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Transcription factor CHREBP regulates ACSL1 mRNA expression in macrophages under high glucose conditions, and NF-κB (p65/RELA) drives ACSL1 mRNA upregulation in response to LPS; both transcription factors bind and activate the Acsl1 promoter at conserved sites.\",\n      \"method\": \"ACSL1 reporter gene assay, ChIP assay, CHREBP/p65 overexpression, bone marrow-derived macrophages from CHREBP KO mice, primary human monocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — promoter reporter, ChIP, and KO macrophages with multiple orthogonal methods\",\n      \"pmids\": [\"36054206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MCL-1 binds ACSL1 through a non-conventional BH3-domain interaction with the BH3-binding hydrophobic groove of MCL-1; genetic loss of Mcl1, mutagenesis, or BH3-mimetic MCL-1 inhibitors repress long-chain (but not short-chain) fatty acid β-oxidation in cells and in mouse livers and hearts.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of BH3 domain, Mcl1 genetic knockout, BH3-mimetic inhibitor treatment, fatty acid oxidation assay in cells and tissues\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal co-IP, mutagenesis, KO, and in vivo functional validation\",\n      \"pmids\": [\"38503284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sortilin (encoded by Sort1) facilitates translocation of ACSL1 from mitochondria to the endolysosomal pathway for degradation in adipocytes; sortilin depletion increases mitochondrial ACSL1, activates AMPK/PGC1α signaling, and promotes beige fat activation and fatty acid oxidation.\",\n      \"method\": \"Sortilin KO in adipocytes, ACSL1 subcellular fractionation, AMPK/PGC1α signaling assays, thermogenic gene expression, HFD mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined molecular mechanism and in vivo metabolic phenotype\",\n      \"pmids\": [\"39232011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1 inhibition (GSK3368715) or PRMT1 knockout upregulates ACSL1 in AML cells by reducing H4R3me2a histone methylation at the ACSL1 promoter, thereby promoting ferroptosis; ACSL1 knockout reverses the ferroptosis sensitivity.\",\n      \"method\": \"PRMT1 KO, GSK3368715 treatment, ChIP for H4R3me2a at ACSL1 promoter, ACSL1 KO epistasis, lipid peroxidation assay, in vivo xenograft\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, epistasis KO, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37144835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 interacts with STAT1 to jointly repress ACSL1 transcription; PRMT6 reduction upregulates ACSL1, increases phospholipid-PUFA production, and drives ferroptosis in diabetic nephropathy; STAT1-specific inhibitor fludarabine reduces ACSL1 expression and delays DN progression.\",\n      \"method\": \"PRMT6 KO mice, transcriptomic and lipidomic analyses, molecular biology assays for PRMT6-STAT1 interaction and ACSL1 transcription, STAT1 inhibitor treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse, transcriptomic/lipidomic validation, mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"39134684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ergosterol directly binds to the C-terminal acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1, stabilizing its closed conformation and allosterically activating its activity; ergosterol is enriched in mitochondria and promotes fatty acid β-oxidation specifically through ACSL1.\",\n      \"method\": \"In vitro binding assay, conformational analysis, structure-activity relationship analysis, ACSL1 KD/KO validation, mitochondrial fractionation, β-oxidation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding and structural analysis with functional validation, single lab\",\n      \"pmids\": [\"39799570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSL1 inhibition or knockdown in macrophages suppresses palmitate-induced foamy/inflammatory phenotype by inhibiting the CD36-FABP4-p38-PPARδ signaling axis; in vivo oral administration of ACSL1 inhibitor triacsin-C in mice before acute high-fat feeding normalized inflammatory/foamy phenotype of circulating monocytes by suppressing FABP4 expression.\",\n      \"method\": \"ACSL1 pharmacological inhibition (triacsin C), siRNA knockdown, signaling pathway analysis, in vivo mouse model with oral triacsin C\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological inhibition with defined signaling pathway, in vivo validation\",\n      \"pmids\": [\"37416456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human gene FACL1 (ACSL1, encoding palmitoyl-CoA ligase) was chromosomally mapped to chromosome region 3q13 by in situ hybridization.\",\n      \"method\": \"In situ hybridization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal localization by in situ hybridization\",\n      \"pmids\": [\"1531127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FATP2 physically interacts with ACSL1 in NSCLC cells (shown by Co-IP); FATP2 silencing combined with ACSL1 overexpression further inhibits proliferation and lipid deposition and promotes fatty acid decomposition, indicating FATP2 regulates lipid metabolism through ACSL1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ACSL1 overexpression (pcDNA-ACSL1), cell proliferation and lipid accumulation assays\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"37172427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 catalyzes monomethylation of H4R3 (H4R3me1) at the HMGB2 promoter, enhancing HMGB2 transcription; HMGB2 then binds the ACSL1 promoter and activates ACSL1 transcription, driving ferroptosis in severe acute pancreatitis.\",\n      \"method\": \"PRMT7 overexpression/inhibition, ChIP for H4R3me1, HMGB2-ACSL1 promoter binding assay, ferroptosis assays in AR42J cells and SAP mouse model\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, promoter binding, epistasis validated in cells and in vivo mouse model\",\n      \"pmids\": [\"38376246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NF-κB directly regulates ACSL1 transcription in liver cancer cells; the oncoprotein HBXIP acts as a coactivator with transcription factor Sp1 by binding the ACSL1 promoter to upregulate ACSL1 mRNA and protein in breast cancer cells.\",\n      \"method\": \"ChIP assay for HBXIP/Sp1 at ACSL1 promoter, HBXIP overexpression/knockdown, NF-κB inhibitor (PDTC), lipid droplet and triglyceride quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP assay identifying transcriptional mechanism, multiple labs reporting NF-κB regulation\",\n      \"pmids\": [\"28132807\", \"28359761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACSL1 overexpression in K562 CML cells induces cellular senescence and inhibits cell growth via the SIRT1/p53/p21 axis; ACSL1 knockdown reverses imatinib-induced senescence.\",\n      \"method\": \"ACSL1 overexpression/knockdown, cell cycle analysis, senescence assays, Western blot for SIRT1/p53/p21 pathway, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function with pathway identification, in vivo validation\",\n      \"pmids\": [\"36289272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACSL1 knockdown in mice (via AAV9) promotes cardiomyocyte cell cycle progression from G0 to G2, enhances myocardial regeneration, and correlates with AKT activation and FOXO1 nuclear exclusion.\",\n      \"method\": \"AAV9-mediated ACSL1 knockdown in mice, RNA-seq of mouse hearts at different developmental ages, cell cycle analysis, AKT/FOXO1 signaling assays, myocardial infarction model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"35122795\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSL1 is a long-chain acyl-CoA synthetase that activates long-chain fatty acids to acyl-CoA thioesters at mitochondrial outer membranes (via N-terminal interaction with CPT1), directing substrates into β-oxidation; its subcellular localization is dynamically regulated (by TBK1 scaffolding and sortilin-mediated lysosomal trafficking), and it participates in diverse cellular processes including ferroptosis (by incorporating PUFAs into triacylglycerols and modulating FSP1 myristoylation), inflammatory signaling (via NF-κB/JNK/ERK cascades downstream of TNFα), skin barrier formation (via linoleic acid activation for ω-O-acylceramide synthesis), and transcriptional regulation by SREBP2, NF-κB, CHREBP, and FXR, while also being stabilized by direct binding to the BH3-binding groove of MCL-1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACSL1 is a long-chain acyl-CoA synthetase that activates fatty acids (C10–C18 saturated and unsaturated) to their CoA thioesters, channeling lipid substrates into β-oxidation, membrane lipid remodeling, and signaling pathways [PMID:8973631, PMID:33152322]. ACSL1 localizes predominantly to the mitochondrial outer membrane via its N-terminal 100 amino acids through interaction with CPT1b, and this localization is dynamically regulated by TBK1 scaffolding (directing substrates toward β-oxidation) and sortilin-mediated endolysosomal trafficking for degradation [PMID:34511469, PMID:33152322, PMID:39232011]. ACSL1 participates in ferroptosis by incorporating polyunsaturated fatty acids into triacylglycerols and by promoting N-myristoylation and membrane targeting of FSP1, and it mediates TNFα-driven inflammatory signaling through the NF-κB/JNK/ERK cascade in monocytes [PMID:33854057, PMID:36882396, PMID:30845379, PMID:37658104]. Acsl1 knockout in mice causes lethal skin barrier defects due to failure of linoleic acid activation required for ω-O-acylceramide synthesis, and MCL-1 directly stabilizes ACSL1 through BH3-groove binding to sustain long-chain fatty acid oxidation in vivo [PMID:34813948, PMID:38503284].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that ACSL1 is a bona fide long-chain acyl-CoA synthetase with defined substrate specificity resolved the enzyme's catalytic identity and showed that all five structural regions are required for activity.\",\n      \"evidence\": \"Recombinant rat ACSL1 purified from E. coli, enzymatic activity assays and deletion mutagenesis\",\n      \"pmids\": [\"8973631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure available\", \"Catalytic mechanism at atomic level unresolved\", \"Isoform-specific substrate channeling not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that ACSL1 catalyzes stereoselective thioesterification of NSAID 2-arylpropionic acids expanded the enzyme's known substrate repertoire beyond endogenous fatty acids to xenobiotic metabolism.\",\n      \"evidence\": \"Purified recombinant ACSL1 kinetic assays with ibuprofen/fenoprofen enantiomers in vitro\",\n      \"pmids\": [\"10725307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance for NSAID chiral inversion not confirmed\", \"Structural basis for stereoselectivity unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that ACSL1 is required for adiponectin/insulin-stimulated AMPK activation in adipocytes linked acyl-CoA synthetase activity to energy-sensing signaling, not just metabolic flux.\",\n      \"evidence\": \"siRNA knockdown in mouse adipocytes with AMP/ATP ratio, AMPK phosphorylation, and fatty acid uptake readouts\",\n      \"pmids\": [\"20667975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACSL1 directly generates AMP or acts indirectly via acyl-CoA consumption unresolved\", \"Contribution relative to FATP1 not fully delineated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolving that ACSL1 localizes to mitochondria (not the plasma membrane) and drives fatty acid uptake via metabolic trapping clarified that ACSL1 promotes uptake indirectly rather than functioning as a transporter.\",\n      \"evidence\": \"Stable overexpression in 3T3-L1 adipocytes and hepatoma cells with confocal microscopy, subcellular fractionation, and uptake assays\",\n      \"pmids\": [\"23024797\", \"22022213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of metabolic trapping at molecular detail unclear\", \"Whether ACSL1 also transiently localizes to other compartments not excluded\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying SREBP2-dependent transcriptional activation of ACSL1 via a sterol regulatory element in its C-promoter revealed how cholesterol homeostasis programs coordinate fatty acid activation.\",\n      \"evidence\": \"Promoter mutagenesis, EMSA, SREBP2 knockdown in HepG2, and in vivo statin/diet models in hamsters and mice\",\n      \"pmids\": [\"26728456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of alternative ACSL1 promoter usage not fully characterized\", \"SREBP1 vs SREBP2 selectivity mechanism unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that hepatic ACSL1 depletion causes hypercholesterolemia and that FXR represses ACSL1 placed ACSL1 within the bile acid–cholesterol regulatory network.\",\n      \"evidence\": \"Adenoviral shRNA knockdown in mouse liver, genome-wide expression profiling, FXR KO mice with agonist treatment\",\n      \"pmids\": [\"30580099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACSL1 regulation by FXR is direct or indirect not fully resolved\", \"Downstream lipid species mediating cholesterol dysregulation not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that ACSL1 is required for TNFα-induced NF-κB-dependent pro-inflammatory monocyte polarization established ACSL1 as a mediator of innate immune activation independent of β-oxidation.\",\n      \"evidence\": \"Triacsin C inhibition and siRNA knockdown in human monocytes with flow cytometry, ELISA, NF-κB reporter and phosphorylation assays\",\n      \"pmids\": [\"30845379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific acyl-CoA species or lipid mediators linking ACSL1 to NF-κB activation not identified\", \"Triacsin C inhibits multiple ACSLs, limiting isoform specificity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering that TBK1 acts as a kinase-independent scaffold to retain ACSL1 at mitochondria during fasting, with loss shifting ACSL1 to the ER, established a regulated mechanism for partitioning fatty acids between oxidation and re-esterification.\",\n      \"evidence\": \"Liver-specific TBK1 KO mice, kinase-dead rescue, co-IP, subcellular fractionation, fatty acid oxidation assays\",\n      \"pmids\": [\"33152322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering TBK1-ACSL1 dissociation upon feeding not defined\", \"Structural basis of TBK1–ACSL1 interaction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping the N-terminal 100 amino acids as necessary and sufficient for mitochondrial targeting via CPT1b interaction explained how ACSL1 couples fatty acid activation to the carnitine shuttle for β-oxidation.\",\n      \"evidence\": \"N-terminal deletion mutagenesis, co-IP with CPT1b, fatty acid oxidation and insulin resistance assays in C2C12 myotubes\",\n      \"pmids\": [\"34511469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TBK1 binding and CPT1b binding overlap or are sequential not tested\", \"Whether all CPT1 isoforms interact equivalently unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that ACSL1 mediates ferroptosis by incorporating conjugated linoleates into triacylglycerols defined a TAG-dependent ferroptosis pathway distinct from GPX4-inhibitor-triggered cell death.\",\n      \"evidence\": \"Genetic manipulation, lipidomics, TAG biosynthesis inhibition, lipid peroxidation and cell death assays, in vivo tumor model\",\n      \"pmids\": [\"33854057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TAG-esterified PUFAs become peroxidized to execute ferroptosis not established\", \"Relative contribution of ACSL1 vs other ACSL isoforms in different tissues unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that Acsl1 knockout mice die with severe skin barrier defects from failed linoleic acid activation and ω-O-acylceramide synthesis revealed a non-redundant developmental role for ACSL1.\",\n      \"evidence\": \"Acsl1 whole-body KO mice, ceramide lipidomics, gene expression profiling\",\n      \"pmids\": [\"34813948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other ACSL isoforms partially compensate in heterozygotes not tested\", \"Cell-type-specific requirements in epidermis not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying CHREBP and NF-κB (p65) as direct transcriptional activators of the Acsl1 promoter in macrophages linked glucose sensing and inflammatory signals to ACSL1 induction via conserved cis-elements.\",\n      \"evidence\": \"ChIP, promoter reporter assays, CHREBP overexpression and KO bone marrow-derived macrophages, primary human monocytes\",\n      \"pmids\": [\"36054206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between CHREBP and NF-κB at the same promoter not resolved\", \"Epigenetic regulation at these sites not explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that ACSL1 promotes FSP1 N-myristoylation, stabilizing FSP1 and enabling its membrane translocation to suppress ferroptosis, revealed a second ferroptosis-related mechanism distinct from TAG incorporation.\",\n      \"evidence\": \"ACSL1 overexpression/knockdown, N-myristoylation and protein stability assays, membrane fractionation, lipid peroxidation assays in ovarian cancer cells\",\n      \"pmids\": [\"36882396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSL1 directly generates myristoyl-CoA for FSP1 modification or acts indirectly not shown\", \"Generalizability beyond ovarian cancer cells untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that PRMT1 inhibition de-represses ACSL1 via reduced H4R3me2a at its promoter, driving ferroptosis in AML cells that is reversed by ACSL1 KO, placed ACSL1 as the effector of PRMT1-regulated ferroptosis.\",\n      \"evidence\": \"PRMT1 KO and inhibitor treatment, ChIP for H4R3me2a, ACSL1 KO epistasis, lipid peroxidation assay, in vivo xenograft\",\n      \"pmids\": [\"37144835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRMT1 directly methylates H4R3 at the ACSL1 locus or acts through intermediary complexes not distinguished\", \"Applicability beyond AML subtype not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering that MCL-1 binds ACSL1 through its BH3-binding groove to stabilize the enzyme and sustain long-chain fatty acid oxidation linked anti-apoptotic BCL-2 family biology to metabolic regulation.\",\n      \"evidence\": \"Reciprocal co-IP, BH3-groove mutagenesis, Mcl1 KO, BH3-mimetic inhibitors, FAO assays in cells and mouse liver/heart\",\n      \"pmids\": [\"38503284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of MCL-1–ACSL1 complex unresolved\", \"Whether MCL-1 binding affects ACSL1 localization or only stability unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying sortilin-mediated translocation of ACSL1 from mitochondria to endolysosomes for degradation revealed a regulated turnover mechanism that controls mitochondrial fatty acid oxidation and beige fat thermogenesis.\",\n      \"evidence\": \"Sortilin KO in adipocytes, ACSL1 subcellular fractionation, AMPK/PGC1α signaling, HFD mouse model\",\n      \"pmids\": [\"39232011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sorting signals on ACSL1 recognized by sortilin not mapped\", \"Whether other ACSL isoforms are similarly regulated by sortilin unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that ergosterol directly binds the C-terminal ASLD1 domain of ACSL1 and allosterically stabilizes a closed, active conformation identified a sterol ligand that positively regulates enzymatic activity.\",\n      \"evidence\": \"In vitro binding assays, conformational analysis, structure-activity studies, ACSL1 KD/KO validation, β-oxidation assays\",\n      \"pmids\": [\"39799570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of ergosterol (a fungal sterol) to mammalian ACSL1 regulation unclear\", \"Whether endogenous mammalian sterols act analogously not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific acyl-CoA products that mediate ACSL1's activation of NF-κB/JNK signaling, the structural basis of the ACSL1–CPT1b and ACSL1–TBK1 complexes, and how TAG-incorporated PUFAs generated by ACSL1 are converted to lipid peroxides to execute ferroptosis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of mammalian ACSL1 or its complexes\", \"Lipid mediator identity downstream of ACSL1 in inflammatory signaling unknown\", \"Mechanism linking ACSL1-generated TAG-PUFAs to ferroptotic peroxidation not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 5, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 7, 8, 12, 16, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 9, 18, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 13, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CPT1B\",\n      \"TBK1\",\n      \"MCL1\",\n      \"SORT1\",\n      \"FSP1\",\n      \"FATP1\",\n      \"FATP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}