{"gene":"ACSL1","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":1996,"finding":"Rat ACSL1 (ACS1) is an acyl-CoA synthetase that activates long-chain fatty acids (C10–C18 saturated; palmitoleate, oleate, linoleate preferred among unsaturated) to acyl-CoA thioesters. Purified recombinant enzyme showed specific activity of 26.2 µmol/min/mg. Deletion mutagenesis of five structural regions (NH2-terminus, two luciferase-like regions, linker, COOH-terminus) showed all five regions are required for enzymatic activity.","method":"Recombinant protein overexpression in E. coli, purification to homogeneity, in vitro enzymatic assay, deletion mutagenesis","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted purified enzyme with substrate specificity measurements and domain-deletion mutagenesis in a single rigorous study","pmids":["8973631"],"is_preprint":false},{"year":2000,"finding":"Purified recombinant rat ACSL1 (ACS1) efficiently catalyzes thioesterification of 2-arylpropionic acid NSAIDs (ibuprofen, fenoprofen), with marked stereoselectivity for the (-)R-enantiomers, identifying ACSL1 as the major enzyme responsible for the first step of chiral inversion of these drugs in liver.","method":"Recombinant ACS1 overexpressed in E. coli, purified to homogeneity, in vitro Michaelis-Menten kinetic assays with R- and S-enantiomers","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted purified enzyme, kinetic parameters with stereoselectivity, single lab but multiple substrates and rigorous quantitative assay","pmids":["10725307"],"is_preprint":false},{"year":1992,"finding":"The human ACSL1 gene (FACL1) was chromosomally localized to region 3q13 by in situ hybridization.","method":"In situ hybridization on human chromosomes","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct chromosomal localization experiment, single lab, single method","pmids":["1531127"],"is_preprint":false},{"year":2011,"finding":"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in both HuH7 and HepG2 hepatoma cells as shown by confocal double immunofluorescence and subcellular fractionation, and its overexpression increases acyl-CoA synthetase activity and long-chain fatty acid ([3H]-oleic acid and Bodipy-C12) uptake, suggesting metabolic trapping as the mechanism driving FA uptake.","method":"Confocal immunofluorescence with organelle markers, subcellular fractionation, enzymatic activity assay, radiolabeled and fluorescent fatty acid uptake assay in overexpressing cells","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, two orthogonal methods (imaging + fractionation), single lab","pmids":["22022213"],"is_preprint":false},{"year":2012,"finding":"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in 3T3-L1 adipocytes as confirmed by confocal microscopy and subcellular fractionation, and increases fatty acid uptake by an indirect metabolic trapping mechanism rather than direct transport at the plasma membrane.","method":"Retroviral stable overexpression in 3T3-L1 adipocytes, confocal microscopy, subcellular fractionation, acyl-CoA synthetase activity assay, fluorescent fatty acid uptake assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct organelle localization with orthogonal methods and functional consequence, single lab","pmids":["23024797"],"is_preprint":false},{"year":2010,"finding":"ACSL1 (along with FATP1) is required for AMPK activation by adiponectin and insulin in mouse adipocytes. Knockdown of Acsl1 blunted the ~2-fold rise in AMP/ATP ratio and AMPK phosphorylation triggered by adiponectin, and also reduced stimulated long-chain fatty acid uptake, placing ACSL1 activity upstream of AMP generation that activates AMPK.","method":"siRNA knockdown in 3T3-L1 adipocytes, AMP/ATP ratio measurement, AMPK phosphorylation by Western blot, radiolabeled fatty acid uptake assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with multiple orthogonal functional readouts, single lab","pmids":["20667975"],"is_preprint":false},{"year":2020,"finding":"TBK1 acts as a scaffolding protein to localize ACSL1 to mitochondria, promoting acyl-CoA generation channeled to β-oxidation. Unphosphorylated (inactive) TBK1 during fasting binds ACSL1 with high affinity at mitochondria; in TBK1-deficient liver, ACSL1 shifts to the ER, redirecting fatty acids from oxidation toward re-esterification and causing hepatic lipid accumulation. Kinase-dead TBK1 rescues fatty acid oxidation, confirming the scaffolding (non-kinase) role.","method":"Liver-specific TBK1 knockout mice, Co-immunoprecipitation of TBK1–ACSL1 complex, subcellular fractionation, fatty acid oxidation assay, rescue with kinase-dead TBK1 expression, isotope tracing (13C)","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO + Co-IP + localization fractionation + isotope tracing + kinase-dead rescue, multiple orthogonal methods in a single rigorous study","pmids":["33152322"],"is_preprint":false},{"year":2021,"finding":"ACSL1 mediates ferroptotic cell death triggered by conjugated linolenic acid αESA by promoting its incorporation into neutral lipids including triacylglycerols. ACSL1 loss-of-function suppressed αESA-induced lipid peroxidation and ferroptosis; interference with triacylglycerol biosynthesis suppressed αESA-triggered (but not GPX4 inhibitor-triggered) ferroptosis.","method":"Genetic knockdown/knockout of ACSL1, lipidomics, lipid peroxidation assays, cell viability assays, pharmacologic inhibition of TG biosynthesis in diverse cancer cell types and mouse tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with defined lipid peroxidation phenotype, lipidomics, pharmacological epistasis, replicated across multiple cell types and in vivo","pmids":["33854057"],"is_preprint":false},{"year":2021,"finding":"ACSL1 localizes to the outer mitochondrial membrane via interaction of its N-terminal 100 amino acids with CPT1b in C2C12 myotubes. An N-terminal deletion mutant (Δ1-100) failed to localize to mitochondria and did not increase fatty acid oxidation, whereas wild-type ACSL1 overexpression increased FAO rates and ameliorated palmitate-induced insulin resistance.","method":"N-terminal deletion mutagenesis, co-immunoprecipitation of ACSL1 with CPT1b, confocal microscopy for localization, Seahorse fatty acid oxidation assay, insulin signaling assay in C2C12 myotubes","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain mutagenesis + Co-IP + direct localization + functional FAO assay, multiple orthogonal methods, single lab","pmids":["34511469"],"is_preprint":false},{"year":2016,"finding":"SREBP2 directly activates transcription of the C-ACSL1 transcript variant through a sterol regulatory element (SRE) motif in the ACSL1 C-promoter. Demonstrated by promoter-activity assays with mutated SRE, DNA-binding assays, and SREBP2 knockdown reducing ACSL1 mRNA and protein. Rosuvastatin-induced SREBP2 activation increased hepatic acyl-CoA synthetase activity and changed cholesterol ester/free cholesterol distribution.","method":"Promoter-luciferase reporter assay with SRE site mutagenesis, EMSA/DNA-binding assay, siRNA knockdown of SREBP2 in HepG2, in vivo rosuvastatin and high-cholesterol/fat diet mouse/hamster models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — promoter mutagenesis + DNA binding assay + genetic knockdown + in vivo validation, multiple orthogonal methods, replicated across two species","pmids":["26728456"],"is_preprint":false},{"year":2018,"finding":"Hepatic ACSL1 is required for bile acid biosynthesis: adenovirus-mediated ACSL1 knockdown in mice caused hypercholesterolemia with elevated LDL-C, suppressed SREBP2 pathway and LDL receptor, and reduced liver bile acid levels with altered bile acid composition. Furthermore, ACSL1 is a transcriptional target of the farnesoid X receptor (FXR); FXR agonist obeticholic acid repressed ACSL1 in wild-type but not FXR-knockout mice.","method":"Adenoviral shRNA knockdown of ACSL1 in mice (HFD and normal chow), genome-wide gene expression profiling, lipid and bile acid quantification, FXR knockout mouse model with FXR agonist treatment","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockdown with multiple metabolic phenotypes, genome-wide expression data, genetic validation with FXR KO, replicated across diet conditions","pmids":["30580099"],"is_preprint":false},{"year":2024,"finding":"MCL-1 binds to ACSL1 via ACSL1's non-conventional BH3-domain interacting with MCL-1's BH3-binding hydrophobic groove. This interaction supports long-chain (but not short-chain) fatty acid β-oxidation in cells, mouse livers, and hearts. Genetic loss of Mcl1, BH3 mutagenesis, or selective BH3-mimetic MCL-1 inhibitors all repressed long-chain FAO, linking MCL-1's anti-apoptotic groove to mitochondrial metabolism.","method":"Co-immunoprecipitation of MCL-1–ACSL1 complex, BH3-domain mutagenesis, Mcl1 conditional knockout in mice, BH3-mimetic inhibitor treatment, Seahorse fatty acid oxidation assays in cells, mouse liver and heart tissues","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, domain mutagenesis, genetic KO, selective inhibitors, functional FAO assays across multiple cell types and in vivo tissues","pmids":["38503284"],"is_preprint":false},{"year":2024,"finding":"Sortilin (encoded by Sort1) facilitates translocation of mitochondrial ACSL1 to the endolysosomal pathway for degradation in adipocytes, thereby reducing ACSL1-mediated fatty acid β-oxidation. Sortilin depletion in adipocytes increases mitochondrial ACSL1 abundance, activates AMPK/PGC1α signaling, promotes beige fat activation, and prevents HFD-induced obesity and insulin resistance in mice.","method":"Sort1 knockout/knockdown in adipocytes and mice, subcellular fractionation, Western blot for mitochondrial ACSL1, co-localization microscopy, AMPK/PGC1α signaling assays, metabolic phenotyping of HFD mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with direct subcellular localization data, downstream signaling assays, and in vivo metabolic phenotype, multiple orthogonal methods","pmids":["39232011"],"is_preprint":false},{"year":2021,"finding":"Acsl1 knockout in mice causes severe skin barrier defects and embryonic lethality. Acsl1 deficiency markedly reduces ω-O-acylceramide (Cer[EOS]) synthesis by failing to activate linoleic acid for ω-O-esterification of ceramide precursors, while Cer[OS] (the precursor) accumulates. Triglyceride species containing linoleic acid are also reduced, implicating TG as a reservoir for linoleic acid channeled by Acsl1 into Cer[EOS] biosynthesis.","method":"Systemic Acsl1 knockout mice, ceramide and triglyceride lipidomics, immunofluorescence for Acsl1 expression in epidermis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 / Strong — whole-body KO with lipidomic mechanistic dissection of ceramide synthesis pathway, clear genetic phenotype","pmids":["34813948"],"is_preprint":false},{"year":2020,"finding":"ACSL1 promotes ovarian cancer metastasis by increasing protein N-myristoylation of substrates (via increased myristic acid activation), activating AMP-activated protein kinase and Src signaling pathways, and enhancing fatty acid β-oxidation.","method":"Shotgun proteomics comparing metastatic vs non-metastatic cells, ACSL1 overexpression/knockdown, lipidomics, AMPK and Src pathway western blotting, myristoylation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with multiple pathway readouts and lipidomics, single lab","pmids":["33082557"],"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 increasing cellular antioxidant capacity and resistance to ferroptosis in ovarian cancer cells.","method":"Genetic manipulation of ACSL1 (overexpression/knockdown), lipid oxidation assays (4-HNE), FSP1 protein stability and localization assays, N-myristoylation detection, ferroptosis resistance assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with mechanistic protein stability and localization data, single lab, multiple methods","pmids":["36882396"],"is_preprint":false},{"year":2019,"finding":"TNFα-induced pro-inflammatory phenotypic shift in monocytes (CD16, CD11b, CD11c, HLA-DR upregulation; IL-1β, MCP-1 secretion) requires ACSL1 activity and acts upstream of NF-κB activation. ACSL1 inhibition (triacsin C) or siRNA knockdown blocked TNFα-induced NF-κB phosphorylation and inflammatory marker expression; β-oxidation and ceramide biosynthesis inhibition had no such effect.","method":"Pharmacological ACSL1 inhibition (triacsin C), siRNA knockdown in THP-1 monocytes and primary human monocytes, flow cytometry, ELISA, NF-κB reporter assay, Western blot for NF-κB phosphorylation","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological + genetic knockdown convergent results, multiple inflammatory readouts, single lab","pmids":["30845379"],"is_preprint":false},{"year":2023,"finding":"TNFα-mediated MMP-9 expression and secretion in monocytic cells requires ACSL1, acting through the JNK/ERK/NF-κB signaling axis. ACSL1 inhibition or knockdown reduced TNFα-induced phosphorylation of SAPK/JNK, c-Jun, ERK1/2, and NF-κB p65, and NF-κB/AP-1 reporter activity. β-oxidation and ceramide biosynthesis inhibition did not affect MMP-9.","method":"Triacsin C pharmacological inhibition, siRNA knockdown of ACSL1 in THP-1 and primary monocytes, qRT-PCR, ELISA, Western blot for pathway phosphorylation, NF-κB/AP-1 reporter assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent pharmacological and genetic approaches with defined pathway epistasis, single lab","pmids":["37658104"],"is_preprint":false},{"year":2023,"finding":"ACSL1 promotes foamy/inflammatory macrophage phenotype via the CD36-FABP4-p38-PPARδ signaling axis. Palmitate-induced ACSL1 upregulation drives macrophage foaming and inflammation; ACSL1 inhibition or knockdown suppressed this phenotype by downregulating FABP4 expression. In vivo, oral triacsin-C administration normalized the inflammatory/foamy monocyte phenotype under acute high-fat feeding.","method":"Pharmacological ACSL1 inhibition (triacsin C), siRNA knockdown in THP-1 and primary human monocytes, flow cytometry, ELISA, Western blot, in vivo oral triacsin-C in mice with acute HFF","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent in vitro and in vivo genetic/pharmacologic approaches with defined signaling pathway, single lab","pmids":["37416456"],"is_preprint":false},{"year":2022,"finding":"ACSL1 transcription in macrophages is induced by high glucose via the carbohydrate response element binding protein (CHREBP) and by LPS-induced inflammation via NF-κB (p65/RELA). Both transcription factors occupy the Acsl1 promoter in BMDMs and increase Acsl1 promoter reporter activity. LPS also increases ACSL1 protein localization to membranes.","method":"Acsl1 reporter gene (promoter + upstream region) assays, ChIP for CHREBP and p65 binding to Acsl1 promoter in mouse BMDMs, siRNA knockdown, Western blot, RT-PCR in primary human monocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays plus genetic knockdown, single lab, multiple methods","pmids":["36054206"],"is_preprint":false},{"year":2017,"finding":"Oncoproteins HBXIP upregulates ACSL1 transcription in breast cancer cells by acting as a coactivator with transcription factor Sp1, which binds the ACSL1 promoter. ChIP assays confirmed HBXIP–Sp1 occupancy at the ACSL1 promoter; HBXIP knockdown reduced ACSL1 mRNA and protein.","method":"ChIP assay for HBXIP/Sp1 at ACSL1 promoter, siRNA knockdown of HBXIP, overexpression of HBXIP, RT-PCR, Western blot, immunohistochemistry in clinical breast cancer tissues","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus gain/loss-of-function, single lab","pmids":["28132807"],"is_preprint":false},{"year":2023,"finding":"PRMT1 inhibition (GSK3368715) or PRMT1 knockout upregulates ACSL1 expression to promote ferroptosis sensitivity in AML cells. Mechanistically, PRMT1 controls H4R3me2a abundance at the ACSL1 promoter; GSK3368715 reduced H4R3me2a genome-wide and at the ACSL1 promoter, increasing ACSL1 expression. ACSL1 knockout reversed the ferroptosis sensitization caused by PRMT1 inhibition.","method":"PRMT1 inhibitor treatment, PRMT1 CRISPR knockout, ACSL1 CRISPR knockout, histone ChIP-seq for H4R3me2a, lipid peroxidation and ferroptosis assays in vitro and in vivo","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — histone ChIP-seq at ACSL1 promoter + double genetic KO epistasis + functional ferroptosis assay, single lab","pmids":["37144835"],"is_preprint":false},{"year":2024,"finding":"PRMT6 interacts with STAT1 to co-regulate ACSL1 transcription. PRMT6 reduction leads to ACSL1 upregulation and increased lipid peroxidation/ferroptosis in diabetic nephropathy. PRMT6 knockout mice showed increased renal ferroptosis that was reduced by the STAT1 inhibitor fludarabine, placing PRMT6/STAT1 upstream of ACSL1 transcription.","method":"PRMT6 knockout mice (DN model), transcriptomic and lipidomic analyses, molecular biology assays for STAT1–PRMT6 interaction and ACSL1 transcription regulation, pharmacological STAT1 inhibition","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo with transcriptomic/lipidomic data and pharmacological epistasis, single lab","pmids":["39134684"],"is_preprint":false},{"year":2024,"finding":"PRMT7 catalyzes H4R3me1 at the HMGB2 promoter, enhancing HMGB2 transcription; HMGB2 then directly binds the ACSL1 promoter to activate ACSL1 transcription, inducing ferroptosis in pancreatic acinar cells during severe acute pancreatitis. PRMT7 inhibition alleviated ferroptosis by suppressing the HMGB2-ACSL1 pathway.","method":"PRMT7 overexpression/inhibition in AR42J cells and SAP mouse model, ChIP for H4R3me1 at HMGB2 promoter and HMGB2 binding at ACSL1 promoter, ferroptosis assays, lipid peroxidation measurement","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for transcriptional cascade + genetic gain/loss-of-function + functional ferroptosis assay, single lab","pmids":["38376246"],"is_preprint":false},{"year":2025,"finding":"Ergosterol directly binds to ACSL1, targeting a drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) and stabilizing the closed conformation of ACSL1's C-terminal domain, allosterically maintaining enzymatic activity. Ergosterol is enriched in mitochondria and promotes fatty acid β-oxidation through this ACSL1 allosteric activation mechanism.","method":"In vitro binding/structural studies (conformational change analysis), structure-activity relationship analysis of sterols vs ACSL1 and SCAP, cellular fatty acid β-oxidation assays, mitochondrial enrichment assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct binding and conformational change data with functional FAO readout, but structural details limited by abstract description; single lab","pmids":["39799570"],"is_preprint":false},{"year":2025,"finding":"In Parkinson's disease microglia, activated TBK1 promotes ACSL1 enrichment on the ER (opposite to its hepatic fasting role), where ACSL1 generates acyl-CoA channeled into lipid droplet biogenesis. ACSL1 overexpression also promotes TBK1 K63-ubiquitination via Nrdp1, creating a feedforward loop. NF-κB directly binds the ACSL1 promoter to drive transcription in microglia.","method":"Single-nucleus RNA-seq, gain/loss-of-function experiments, TBK1 activation studies, Nrdp1 ubiquitination assay, ChIP for NF-κB at ACSL1 promoter, lipid droplet quantification, dopaminergic neuron death assay","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (ubiquitination, ChIP, localization, functional) in a single study, single lab","pmids":["40684214"],"is_preprint":false},{"year":2025,"finding":"Impaired hepatic ketogenesis (via HMGCS2 loss) causes excess acetyl-CoA accumulation that drives ACSL1 translocation to the ER, where ACSL1-mediated fatty acid re-esterification promotes hepatic steatosis. L-carnitine, which buffers acetyl-CoA, reduces ER-associated ACSL1 and alleviates steatosis.","method":"Liver-specific HMGCS2 knockout mice, Western blot for ACSL1 subcellular fractionation (ER vs mitochondria), L-carnitine rescue experiment, human primary hepatocytes, histologic analysis of human MASH samples","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO + subcellular fractionation + pharmacological rescue + human tissue validation, single lab but multiple approaches","pmids":["40692014"],"is_preprint":false},{"year":2023,"finding":"FATP2 (SLC27A2) physically interacts with ACSL1 in non-small cell lung cancer cells, as shown by Co-IP. Co-transfection of si-FATP2 with pcDNA-ACSL1 further inhibited proliferation and lipid deposition and promoted fatty acid decomposition, indicating FATP2 regulates lipid metabolism through ACSL1.","method":"Co-immunoprecipitation (FATP2–ACSL1 interaction), siRNA knockdown of FATP2, ACSL1 overexpression, cell proliferation and lipid deposition assays","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, functional assays without deep mechanistic characterization, single lab","pmids":["37172427"],"is_preprint":false},{"year":2022,"finding":"ACSL1 knockdown in neonatal mouse cardiomyocytes and via AAV9 in adult mice promoted cell cycle progression from G0 to G2 phase, enhanced myocardial regeneration, and improved cardiac function after MI, associated with AKT activation and FOXO1 nuclear exclusion.","method":"AAV9-mediated ACSL1 knockdown in mice, primary cardiomyocyte culture, cell cycle analysis, AKT/FOXO1 pathway Western blot, cardiac function assessment (echocardiography), myocardial infarction model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV knockdown + in vitro cell cycle mechanistic data + defined signaling pathway, single lab","pmids":["35122795"],"is_preprint":false},{"year":2021,"finding":"ACSL1 inhibition (triacsin C) or knockdown suppressed acetate-plus-TNFα-synergized MCP-1 production in monocytes through the ACSL1/MAPK/NF-κB axis; ACSL1 inhibition reduced p38 MAPK, ERK1/2, and NF-κB phosphorylation and NF-κB/AP-1 activity. Neither CPT-I nor SPT inhibition recapitulated this effect, placing acyl-CoA formation specifically upstream.","method":"Pharmacological ACSL1 inhibition, siRNA knockdown in THP-1 monocytes, ELISA, qRT-PCR, Western blot for MAPK/NF-κB pathway phosphorylation, NF-κB/AP-1 reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent pharmacological/genetic approaches with mechanistic pathway epistasis, single lab","pmids":["34299302"],"is_preprint":false}],"current_model":"ACSL1 is a long-chain acyl-CoA synthetase that activates free fatty acids (preferring C10–C18 substrates including linoleate) to acyl-CoA thioesters; its subcellular localization—dynamically regulated at mitochondria vs. ER by scaffolding interactions with TBK1 or sortilin, and by the cellular acetyl-CoA pool—determines whether acyl-CoAs are channeled toward β-oxidation or lipid re-esterification/droplet biogenesis. At mitochondria, ACSL1 interacts with CPT1b (via its N-terminal 100 aa) and with MCL-1 (via a non-canonical BH3-domain) to support long-chain FAO; at the ER it promotes re-esterification and lipid droplet formation. ACSL1 also drives ferroptosis by incorporating polyunsaturated fatty acids into triacylglycerols for lipid peroxidation, mediates protein N-myristoylation, and acts upstream of NF-κB/MAPK inflammatory signaling in monocytes; its transcription is controlled by SREBP2 (via SRE), CHREBP (high glucose), NF-κB (LPS), and epigenetic regulators including PRMT1/H4R3me2a and the PRMT7/HMGB2 axis."},"narrative":{"mechanistic_narrative":"ACSL1 is a long-chain acyl-CoA synthetase that activates free fatty acids (C10–C18 saturated, plus palmitoleate, oleate, and linoleate) to acyl-CoA thioesters, the committed first step that channels fatty acids into oxidative and biosynthetic fates [PMID:8973631]. Its enzymatic activity requires all five structural regions of the protein and can be allosterically tuned by direct sterol binding to a pocket in its acetyl-CoA synthetase-like domain [PMID:8973631, PMID:39799570], and it also thioesterifies xenobiotic 2-arylpropionic acid NSAIDs with stereoselectivity, mediating their chiral inversion [PMID:10725307]. The central organizing principle of ACSL1 biology is that its subcellular partitioning between mitochondria and ER dictates metabolic outcome: mitochondrial scaffolding by unphosphorylated TBK1 and by an interaction of its N-terminal 100 residues with CPT1b localizes ACSL1 to the outer mitochondrial membrane to drive β-oxidation, whereas loss of this scaffolding, sortilin-mediated endolysosomal degradation, or acetyl-CoA accumulation redirects ACSL1 to the ER toward fatty acid re-esterification, lipid droplet biogenesis, and hepatic steatosis [PMID:33152322, PMID:34511469, PMID:39232011, PMID:40692014]. MCL-1 binds ACSL1 through a non-canonical BH3 interaction with its anti-apoptotic groove and is specifically required for long-chain FAO [PMID:38503284]. By trapping fatty acids as acyl-CoAs, ACSL1 promotes cellular fatty acid uptake and supplies AMP that activates AMPK signaling [PMID:22022213, PMID:20667975]. ACSL1 channels linoleate into ω-O-acylceramide synthesis essential for the skin barrier, and its genetic loss causes embryonic lethality and barrier defects in mice [PMID:34813948]. Through incorporation of polyunsaturated fatty acids into triacylglycerols it drives lipid peroxidation and ferroptosis [PMID:33854057], while in cancer cells its production of myristoyl-CoA supports protein N-myristoylation that stabilizes FSP1 and confers ferroptosis resistance [PMID:33082557, PMID:36882396]. In monocytes and macrophages ACSL1 acts upstream of MAPK/NF-κB inflammatory signaling independently of β-oxidation or ceramide synthesis [PMID:30845379, PMID:34299302]. ACSL1 transcription is controlled by SREBP2 via a sterol regulatory element, by FXR, CHREBP, and NF-κB, and by epigenetic regulators including PRMT1-controlled H4R3 methylation at its promoter [PMID:26728456, PMID:30580099, PMID:36054206, PMID:37144835].","teleology":[{"year":1996,"claim":"Established ACSL1 as a bona fide long-chain acyl-CoA synthetase with defined substrate preference and a multi-region structural requirement for catalysis, answering what reaction the enzyme performs.","evidence":"Purified recombinant rat enzyme, in vitro activity assays, and deletion mutagenesis of five structural regions","pmids":["8973631"],"confidence":"High","gaps":["Did not resolve subcellular targeting or physiological substrate channeling","No high-resolution structure of the catalytic mechanism"]},{"year":2000,"claim":"Extended ACSL1 substrate scope to xenobiotics, showing it stereoselectively thioesterifies 2-arylpropionic NSAIDs and mediates their chiral inversion in liver.","evidence":"Purified recombinant enzyme with Michaelis-Menten kinetics on R/S enantiomers","pmids":["10725307"],"confidence":"High","gaps":["In vitro only; physiological contribution in vivo not quantified"]},{"year":2011,"claim":"Linked ACSL1 localization to function, showing mitochondrial ACSL1 drives fatty acid uptake by metabolic trapping rather than acting as a plasma-membrane transporter.","evidence":"Confocal imaging, subcellular fractionation, and radiolabeled/fluorescent FA uptake assays in hepatoma cells and adipocytes","pmids":["22022213","23024797"],"confidence":"Medium","gaps":["Based on overexpression, which may bias localization","Did not address what controls mitochondrial vs ER targeting"]},{"year":2010,"claim":"Placed ACSL1 enzymatic activity upstream of AMPK activation, connecting fatty acid activation to energy-sensing signaling.","evidence":"siRNA knockdown in adipocytes with AMP/ATP and AMPK phosphorylation readouts","pmids":["20667975"],"confidence":"Medium","gaps":["Mechanism linking acyl-CoA synthesis to AMP generation not fully resolved"]},{"year":2016,"claim":"Identified direct transcriptional control of ACSL1 by SREBP2 through a sterol regulatory element, tying ACSL1 expression to cholesterol/lipid homeostasis.","evidence":"Promoter reporter with SRE mutagenesis, DNA-binding assay, SREBP2 knockdown, and in vivo statin models in two species","pmids":["26728456"],"confidence":"High","gaps":["Restricted to the C-promoter transcript variant","Did not address other promoter elements"]},{"year":2018,"claim":"Showed hepatic ACSL1 is required for bile acid biosynthesis and is itself an FXR target, embedding it in a feedback loop with sterol/bile acid metabolism.","evidence":"Adenoviral ACSL1 knockdown in mice, genome-wide expression, bile acid quantification, and FXR-KO with agonist treatment","pmids":["30580099"],"confidence":"High","gaps":["Whether ACSL1 acts directly in bile acid synthesis or indirectly via SREBP2 not separated"]},{"year":2019,"claim":"Defined a metabolism-independent role for ACSL1 upstream of NF-κB in inflammatory activation of monocytes.","evidence":"Triacsin C inhibition and siRNA in THP-1/primary monocytes with NF-κB and inflammatory marker readouts; β-oxidation and ceramide inhibition as controls","pmids":["30845379"],"confidence":"Medium","gaps":["The acyl-CoA species or lipid signal driving NF-κB not identified","Direct molecular link between acyl-CoA and NF-κB unknown"]},{"year":2020,"claim":"Established the scaffolding paradigm: unphosphorylated TBK1 anchors ACSL1 at mitochondria to favor β-oxidation, with loss of scaffolding shifting ACSL1 to the ER and re-esterification.","evidence":"Liver-specific TBK1 KO, Co-IP, fractionation, 13C tracing, and kinase-dead rescue","pmids":["33152322"],"confidence":"High","gaps":["Structural basis of the TBK1–ACSL1 interaction not resolved","How fasting state controls TBK1 phosphorylation/ACSL1 binding incompletely mapped"]},{"year":2020,"claim":"Connected ACSL1 to protein N-myristoylation, revealing a non-classical output of its acyl-CoA synthesis in driving cancer metastasis.","evidence":"Proteomics, gain/loss-of-function, lipidomics, myristoylation assay, AMPK/Src readouts in ovarian cancer cells","pmids":["33082557"],"confidence":"Medium","gaps":["Specific myristoylated substrates beyond pathway-level readouts limited at this stage"]},{"year":2021,"claim":"Defined ACSL1 as a driver of ferroptosis by incorporating PUFAs into triacylglycerols that fuel lipid peroxidation, distinguishing this from GPX4-axis ferroptosis.","evidence":"Genetic loss-of-function, lipidomics, lipid peroxidation assays, and TG-biosynthesis pharmacologic epistasis across cell types and a tumor model","pmids":["33854057"],"confidence":"High","gaps":["How TG-stored PUFAs are mobilized for peroxidation not detailed"]},{"year":2021,"claim":"Mapped the N-terminal 100 residues as the CPT1b-binding mitochondrial targeting determinant required for ACSL1-supported FAO.","evidence":"N-terminal deletion mutagenesis, Co-IP with CPT1b, confocal localization, and Seahorse FAO assays in C2C12 myotubes","pmids":["34511469"],"confidence":"High","gaps":["Whether CPT1b binding is required in tissues other than muscle unknown"]},{"year":2021,"claim":"Demonstrated ACSL1 is essential for ω-O-acylceramide synthesis and the skin barrier by activating linoleate, explaining its requirement for viability.","evidence":"Systemic Acsl1 KO mice with ceramide/TG lipidomics and epidermal immunofluorescence","pmids":["34813948"],"confidence":"High","gaps":["Relative contributions of barrier defect vs other functions to embryonic lethality not dissected"]},{"year":2022,"claim":"Implicated ACSL1 as a brake on cardiomyocyte cell-cycle re-entry, linking its loss to myocardial regeneration via AKT/FOXO1.","evidence":"AAV9 knockdown in mice, cell-cycle analysis, AKT/FOXO1 Western blot, and post-MI cardiac function assessment","pmids":["35122795"],"confidence":"Medium","gaps":["Metabolic vs signaling basis of the cell-cycle effect not separated"]},{"year":2023,"claim":"Extended the inflammatory role of ACSL1 to MMP-9 and macrophage foaming, defining JNK/ERK/NF-κB and CD36-FABP4-p38-PPARδ axes downstream.","evidence":"Triacsin C and siRNA in monocytes with pathway phosphorylation, reporter assays, and in vivo oral inhibitor in high-fat-fed mice","pmids":["37658104","37416456","34299302"],"confidence":"Medium","gaps":["Direct acyl-CoA-derived signal initiating MAPK/NF-κB not identified"]},{"year":2023,"claim":"Identified FSP1 as a myristoylation substrate stabilized by ACSL1, explaining how ACSL1 can confer ferroptosis resistance in addition to driving it.","evidence":"ACSL1 gain/loss-of-function with FSP1 stability, localization, and N-myristoylation assays in ovarian cancer cells","pmids":["36882396"],"confidence":"Medium","gaps":["Reconciliation of pro- vs anti-ferroptotic ACSL1 roles context-dependent and not unified mechanistically"]},{"year":2023,"claim":"Expanded the transcriptional control of ACSL1 to glucose (CHREBP) and inflammatory (NF-κB) inputs and additional oncogenic coactivators.","evidence":"ChIP and reporter assays for CHREBP/p65 in BMDMs; ChIP for HBXIP/Sp1 at the ACSL1 promoter in breast cancer cells","pmids":["36054206","28132807"],"confidence":"Medium","gaps":["Combinatorial regulation by these factors under physiological conditions not integrated"]},{"year":2024,"claim":"Revealed MCL-1 as a direct ACSL1 partner via a non-canonical BH3 interaction selectively required for long-chain FAO, coupling an anti-apoptotic protein to mitochondrial metabolism.","evidence":"Reciprocal Co-IP, BH3 mutagenesis, Mcl1 conditional KO, BH3-mimetic inhibitors, and Seahorse FAO across cells and tissues","pmids":["38503284"],"confidence":"High","gaps":["Structural detail of how the BH3 interaction promotes FAO not fully defined"]},{"year":2024,"claim":"Defined sortilin-mediated endolysosomal degradation as a route controlling mitochondrial ACSL1 abundance and systemic metabolic phenotype.","evidence":"Sort1 KO/knockdown in adipocytes and mice, fractionation, co-localization, AMPK/PGC1α assays, and HFD metabolic phenotyping","pmids":["39232011"],"confidence":"High","gaps":["Signal triggering sortilin-dependent ACSL1 trafficking unknown"]},{"year":2024,"claim":"Added epigenetic and PRMT-axis control of ACSL1 transcription that tunes ferroptosis sensitivity across disease contexts.","evidence":"PRMT1 inhibitor/KO with H4R3me2a ChIP-seq and ACSL1-KO epistasis in AML; PRMT6/STAT1 in diabetic nephropathy; PRMT7/HMGB2 ChIP cascade in pancreatitis","pmids":["37144835","39134684","38376246"],"confidence":"Medium","gaps":["Whether these PRMT axes converge on shared promoter elements not established","Mostly single-lab, disease-specific observations"]},{"year":2025,"claim":"Provided a structural-allosteric mechanism, showing ergosterol binds an ASLD1 pocket to stabilize ACSL1's closed conformation and sustain activity and mitochondrial FAO.","evidence":"In vitro binding/conformational analysis, sterol structure-activity relationships, and cellular FAO assays","pmids":["39799570"],"confidence":"Medium","gaps":["Atomic-resolution structure of the binding pocket limited","Physiological sterol ligand in mammalian cells not confirmed"]},{"year":2025,"claim":"Showed metabolic state controls ACSL1 ER-targeting: acetyl-CoA accumulation (from impaired ketogenesis) and microglial TBK1 activation redirect ACSL1 to the ER for re-esterification and lipid droplet biogenesis in disease.","evidence":"HMGCS2-KO mice with fractionation and L-carnitine rescue and human MASH samples; snRNA-seq, Nrdp1 ubiquitination, NF-κB ChIP, and lipid droplet assays in PD microglia","pmids":["40692014","40684214"],"confidence":"Medium","gaps":["How acetyl-CoA and TBK1 phosphorylation state mechanistically converge on ACSL1 trafficking not unified","Single-lab disease models"]},{"year":null,"claim":"The molecular switch that integrates scaffolding (TBK1, CPT1b, MCL-1), degradation (sortilin), metabolite sensing (acetyl-CoA, sterols), and post-translational state to set ACSL1's mitochondria-vs-ER partitioning remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model or structure of the targeting determinants","How a single enzyme is partitioned in real time between competing organelles is unknown"]}],"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":[0,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4,6,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,25,26]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,17,18,29]}],"complexes":[],"partners":["TBK1","CPT1B","MCL1","SORT1","SLC27A2"],"other_free_text":[]}},"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; C9D","url":"https://www.omim.org/entry/613825"},{"mim_id":"159552","title":"MYELOID CELL LEUKEMIA SEQUENCE 1; MCL1","url":"https://www.omim.org/entry/159552"},{"mim_id":"152425","title":"ACYL-CoA SYNTHETASE LONG CHAIN FAMILY, MEMBER 1; ACSL1","url":"https://www.omim.org/entry/152425"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":680.0},{"tissue":"liver","ntpm":1068.9},{"tissue":"skeletal 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Purified recombinant enzyme showed specific activity of 26.2 µmol/min/mg. Deletion mutagenesis of five structural regions (NH2-terminus, two luciferase-like regions, linker, COOH-terminus) showed all five regions are required for enzymatic activity.\",\n      \"method\": \"Recombinant protein overexpression in E. coli, purification to homogeneity, in vitro enzymatic assay, deletion mutagenesis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted purified enzyme with substrate specificity measurements and domain-deletion mutagenesis in a single rigorous study\",\n      \"pmids\": [\"8973631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Purified recombinant rat ACSL1 (ACS1) efficiently catalyzes thioesterification of 2-arylpropionic acid NSAIDs (ibuprofen, fenoprofen), with marked stereoselectivity for the (-)R-enantiomers, identifying ACSL1 as the major enzyme responsible for the first step of chiral inversion of these drugs in liver.\",\n      \"method\": \"Recombinant ACS1 overexpressed in E. coli, purified to homogeneity, in vitro Michaelis-Menten kinetic assays with R- and S-enantiomers\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted purified enzyme, kinetic parameters with stereoselectivity, single lab but multiple substrates and rigorous quantitative assay\",\n      \"pmids\": [\"10725307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human ACSL1 gene (FACL1) was chromosomally localized to region 3q13 by in situ hybridization.\",\n      \"method\": \"In situ hybridization on human chromosomes\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct chromosomal localization experiment, single lab, single method\",\n      \"pmids\": [\"1531127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in both HuH7 and HepG2 hepatoma cells as shown by confocal double immunofluorescence and subcellular fractionation, and its overexpression increases acyl-CoA synthetase activity and long-chain fatty acid ([3H]-oleic acid and Bodipy-C12) uptake, suggesting metabolic trapping as the mechanism driving FA uptake.\",\n      \"method\": \"Confocal immunofluorescence with organelle markers, subcellular fractionation, enzymatic activity assay, radiolabeled and fluorescent fatty acid uptake assay in overexpressing cells\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, two orthogonal methods (imaging + fractionation), single lab\",\n      \"pmids\": [\"22022213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpressed ACSL1 localizes to mitochondria (not plasma membrane) in 3T3-L1 adipocytes as confirmed by confocal microscopy and subcellular fractionation, and increases fatty acid uptake by an indirect metabolic trapping mechanism rather than direct transport at the plasma membrane.\",\n      \"method\": \"Retroviral stable overexpression in 3T3-L1 adipocytes, confocal microscopy, subcellular fractionation, acyl-CoA synthetase activity assay, fluorescent fatty acid uptake assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct organelle localization with orthogonal methods and functional consequence, single lab\",\n      \"pmids\": [\"23024797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ACSL1 (along with FATP1) is required for AMPK activation by adiponectin and insulin in mouse adipocytes. Knockdown of Acsl1 blunted the ~2-fold rise in AMP/ATP ratio and AMPK phosphorylation triggered by adiponectin, and also reduced stimulated long-chain fatty acid uptake, placing ACSL1 activity upstream of AMP generation that activates AMPK.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 adipocytes, AMP/ATP ratio measurement, AMPK phosphorylation by Western blot, radiolabeled fatty acid uptake assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"20667975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TBK1 acts as a scaffolding protein to localize ACSL1 to mitochondria, promoting acyl-CoA generation channeled to β-oxidation. Unphosphorylated (inactive) TBK1 during fasting binds ACSL1 with high affinity at mitochondria; in TBK1-deficient liver, ACSL1 shifts to the ER, redirecting fatty acids from oxidation toward re-esterification and causing hepatic lipid accumulation. Kinase-dead TBK1 rescues fatty acid oxidation, confirming the scaffolding (non-kinase) role.\",\n      \"method\": \"Liver-specific TBK1 knockout mice, Co-immunoprecipitation of TBK1–ACSL1 complex, subcellular fractionation, fatty acid oxidation assay, rescue with kinase-dead TBK1 expression, isotope tracing (13C)\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO + Co-IP + localization fractionation + isotope tracing + kinase-dead rescue, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"33152322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSL1 mediates ferroptotic cell death triggered by conjugated linolenic acid αESA by promoting its incorporation into neutral lipids including triacylglycerols. ACSL1 loss-of-function suppressed αESA-induced lipid peroxidation and ferroptosis; interference with triacylglycerol biosynthesis suppressed αESA-triggered (but not GPX4 inhibitor-triggered) ferroptosis.\",\n      \"method\": \"Genetic knockdown/knockout of ACSL1, lipidomics, lipid peroxidation assays, cell viability assays, pharmacologic inhibition of TG biosynthesis in diverse cancer cell types and mouse tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with defined lipid peroxidation phenotype, lipidomics, pharmacological epistasis, replicated across multiple cell types and in vivo\",\n      \"pmids\": [\"33854057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSL1 localizes to the outer mitochondrial membrane via interaction of its N-terminal 100 amino acids with CPT1b in C2C12 myotubes. An N-terminal deletion mutant (Δ1-100) failed to localize to mitochondria and did not increase fatty acid oxidation, whereas wild-type ACSL1 overexpression increased FAO rates and ameliorated palmitate-induced insulin resistance.\",\n      \"method\": \"N-terminal deletion mutagenesis, co-immunoprecipitation of ACSL1 with CPT1b, confocal microscopy for localization, Seahorse fatty acid oxidation assay, insulin signaling assay in C2C12 myotubes\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain mutagenesis + Co-IP + direct localization + functional FAO assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34511469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SREBP2 directly activates transcription of the C-ACSL1 transcript variant through a sterol regulatory element (SRE) motif in the ACSL1 C-promoter. Demonstrated by promoter-activity assays with mutated SRE, DNA-binding assays, and SREBP2 knockdown reducing ACSL1 mRNA and protein. Rosuvastatin-induced SREBP2 activation increased hepatic acyl-CoA synthetase activity and changed cholesterol ester/free cholesterol distribution.\",\n      \"method\": \"Promoter-luciferase reporter assay with SRE site mutagenesis, EMSA/DNA-binding assay, siRNA knockdown of SREBP2 in HepG2, in vivo rosuvastatin and high-cholesterol/fat diet mouse/hamster models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — promoter mutagenesis + DNA binding assay + genetic knockdown + in vivo validation, multiple orthogonal methods, replicated across two species\",\n      \"pmids\": [\"26728456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatic ACSL1 is required for bile acid biosynthesis: adenovirus-mediated ACSL1 knockdown in mice caused hypercholesterolemia with elevated LDL-C, suppressed SREBP2 pathway and LDL receptor, and reduced liver bile acid levels with altered bile acid composition. Furthermore, ACSL1 is a transcriptional target of the farnesoid X receptor (FXR); FXR agonist obeticholic acid repressed ACSL1 in wild-type but not FXR-knockout mice.\",\n      \"method\": \"Adenoviral shRNA knockdown of ACSL1 in mice (HFD and normal chow), genome-wide gene expression profiling, lipid and bile acid quantification, FXR knockout mouse model with FXR agonist treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockdown with multiple metabolic phenotypes, genome-wide expression data, genetic validation with FXR KO, replicated across diet conditions\",\n      \"pmids\": [\"30580099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MCL-1 binds to ACSL1 via ACSL1's non-conventional BH3-domain interacting with MCL-1's BH3-binding hydrophobic groove. This interaction supports long-chain (but not short-chain) fatty acid β-oxidation in cells, mouse livers, and hearts. Genetic loss of Mcl1, BH3 mutagenesis, or selective BH3-mimetic MCL-1 inhibitors all repressed long-chain FAO, linking MCL-1's anti-apoptotic groove to mitochondrial metabolism.\",\n      \"method\": \"Co-immunoprecipitation of MCL-1–ACSL1 complex, BH3-domain mutagenesis, Mcl1 conditional knockout in mice, BH3-mimetic inhibitor treatment, Seahorse fatty acid oxidation assays in cells, mouse liver and heart tissues\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, domain mutagenesis, genetic KO, selective inhibitors, functional FAO assays across multiple cell types and in vivo tissues\",\n      \"pmids\": [\"38503284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sortilin (encoded by Sort1) facilitates translocation of mitochondrial ACSL1 to the endolysosomal pathway for degradation in adipocytes, thereby reducing ACSL1-mediated fatty acid β-oxidation. Sortilin depletion in adipocytes increases mitochondrial ACSL1 abundance, activates AMPK/PGC1α signaling, promotes beige fat activation, and prevents HFD-induced obesity and insulin resistance in mice.\",\n      \"method\": \"Sort1 knockout/knockdown in adipocytes and mice, subcellular fractionation, Western blot for mitochondrial ACSL1, co-localization microscopy, AMPK/PGC1α signaling assays, metabolic phenotyping of HFD mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with direct subcellular localization data, downstream signaling assays, and in vivo metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"39232011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Acsl1 knockout in mice causes severe skin barrier defects and embryonic lethality. Acsl1 deficiency markedly reduces ω-O-acylceramide (Cer[EOS]) synthesis by failing to activate linoleic acid for ω-O-esterification of ceramide precursors, while Cer[OS] (the precursor) accumulates. Triglyceride species containing linoleic acid are also reduced, implicating TG as a reservoir for linoleic acid channeled by Acsl1 into Cer[EOS] biosynthesis.\",\n      \"method\": \"Systemic Acsl1 knockout mice, ceramide and triglyceride lipidomics, immunofluorescence for Acsl1 expression in epidermis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — whole-body KO with lipidomic mechanistic dissection of ceramide synthesis pathway, clear genetic phenotype\",\n      \"pmids\": [\"34813948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACSL1 promotes ovarian cancer metastasis by increasing protein N-myristoylation of substrates (via increased myristic acid activation), activating AMP-activated protein kinase and Src signaling pathways, and enhancing fatty acid β-oxidation.\",\n      \"method\": \"Shotgun proteomics comparing metastatic vs non-metastatic cells, ACSL1 overexpression/knockdown, lipidomics, AMPK and Src pathway western blotting, myristoylation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with multiple pathway readouts and lipidomics, single lab\",\n      \"pmids\": [\"33082557\"],\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 increasing cellular antioxidant capacity and resistance to ferroptosis in ovarian cancer cells.\",\n      \"method\": \"Genetic manipulation of ACSL1 (overexpression/knockdown), lipid oxidation assays (4-HNE), FSP1 protein stability and localization assays, N-myristoylation detection, ferroptosis resistance assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with mechanistic protein stability and localization data, single lab, multiple methods\",\n      \"pmids\": [\"36882396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNFα-induced pro-inflammatory phenotypic shift in monocytes (CD16, CD11b, CD11c, HLA-DR upregulation; IL-1β, MCP-1 secretion) requires ACSL1 activity and acts upstream of NF-κB activation. ACSL1 inhibition (triacsin C) or siRNA knockdown blocked TNFα-induced NF-κB phosphorylation and inflammatory marker expression; β-oxidation and ceramide biosynthesis inhibition had no such effect.\",\n      \"method\": \"Pharmacological ACSL1 inhibition (triacsin C), siRNA knockdown in THP-1 monocytes and primary human monocytes, flow cytometry, ELISA, NF-κB reporter assay, Western blot for NF-κB phosphorylation\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological + genetic knockdown convergent results, multiple inflammatory readouts, single lab\",\n      \"pmids\": [\"30845379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNFα-mediated MMP-9 expression and secretion in monocytic cells requires ACSL1, acting through the JNK/ERK/NF-κB signaling axis. ACSL1 inhibition or knockdown reduced TNFα-induced phosphorylation of SAPK/JNK, c-Jun, ERK1/2, and NF-κB p65, and NF-κB/AP-1 reporter activity. β-oxidation and ceramide biosynthesis inhibition did not affect MMP-9.\",\n      \"method\": \"Triacsin C pharmacological inhibition, siRNA knockdown of ACSL1 in THP-1 and primary monocytes, qRT-PCR, ELISA, Western blot for pathway phosphorylation, NF-κB/AP-1 reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent pharmacological and genetic approaches with defined pathway epistasis, single lab\",\n      \"pmids\": [\"37658104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSL1 promotes foamy/inflammatory macrophage phenotype via the CD36-FABP4-p38-PPARδ signaling axis. Palmitate-induced ACSL1 upregulation drives macrophage foaming and inflammation; ACSL1 inhibition or knockdown suppressed this phenotype by downregulating FABP4 expression. In vivo, oral triacsin-C administration normalized the inflammatory/foamy monocyte phenotype under acute high-fat feeding.\",\n      \"method\": \"Pharmacological ACSL1 inhibition (triacsin C), siRNA knockdown in THP-1 and primary human monocytes, flow cytometry, ELISA, Western blot, in vivo oral triacsin-C in mice with acute HFF\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent in vitro and in vivo genetic/pharmacologic approaches with defined signaling pathway, single lab\",\n      \"pmids\": [\"37416456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACSL1 transcription in macrophages is induced by high glucose via the carbohydrate response element binding protein (CHREBP) and by LPS-induced inflammation via NF-κB (p65/RELA). Both transcription factors occupy the Acsl1 promoter in BMDMs and increase Acsl1 promoter reporter activity. LPS also increases ACSL1 protein localization to membranes.\",\n      \"method\": \"Acsl1 reporter gene (promoter + upstream region) assays, ChIP for CHREBP and p65 binding to Acsl1 promoter in mouse BMDMs, siRNA knockdown, Western blot, RT-PCR in primary human monocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays plus genetic knockdown, single lab, multiple methods\",\n      \"pmids\": [\"36054206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oncoproteins HBXIP upregulates ACSL1 transcription in breast cancer cells by acting as a coactivator with transcription factor Sp1, which binds the ACSL1 promoter. ChIP assays confirmed HBXIP–Sp1 occupancy at the ACSL1 promoter; HBXIP knockdown reduced ACSL1 mRNA and protein.\",\n      \"method\": \"ChIP assay for HBXIP/Sp1 at ACSL1 promoter, siRNA knockdown of HBXIP, overexpression of HBXIP, RT-PCR, Western blot, immunohistochemistry in clinical breast cancer tissues\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus gain/loss-of-function, single lab\",\n      \"pmids\": [\"28132807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1 inhibition (GSK3368715) or PRMT1 knockout upregulates ACSL1 expression to promote ferroptosis sensitivity in AML cells. Mechanistically, PRMT1 controls H4R3me2a abundance at the ACSL1 promoter; GSK3368715 reduced H4R3me2a genome-wide and at the ACSL1 promoter, increasing ACSL1 expression. ACSL1 knockout reversed the ferroptosis sensitization caused by PRMT1 inhibition.\",\n      \"method\": \"PRMT1 inhibitor treatment, PRMT1 CRISPR knockout, ACSL1 CRISPR knockout, histone ChIP-seq for H4R3me2a, lipid peroxidation and ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — histone ChIP-seq at ACSL1 promoter + double genetic KO epistasis + functional ferroptosis assay, single lab\",\n      \"pmids\": [\"37144835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 interacts with STAT1 to co-regulate ACSL1 transcription. PRMT6 reduction leads to ACSL1 upregulation and increased lipid peroxidation/ferroptosis in diabetic nephropathy. PRMT6 knockout mice showed increased renal ferroptosis that was reduced by the STAT1 inhibitor fludarabine, placing PRMT6/STAT1 upstream of ACSL1 transcription.\",\n      \"method\": \"PRMT6 knockout mice (DN model), transcriptomic and lipidomic analyses, molecular biology assays for STAT1–PRMT6 interaction and ACSL1 transcription regulation, pharmacological STAT1 inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo with transcriptomic/lipidomic data and pharmacological epistasis, single lab\",\n      \"pmids\": [\"39134684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 catalyzes H4R3me1 at the HMGB2 promoter, enhancing HMGB2 transcription; HMGB2 then directly binds the ACSL1 promoter to activate ACSL1 transcription, inducing ferroptosis in pancreatic acinar cells during severe acute pancreatitis. PRMT7 inhibition alleviated ferroptosis by suppressing the HMGB2-ACSL1 pathway.\",\n      \"method\": \"PRMT7 overexpression/inhibition in AR42J cells and SAP mouse model, ChIP for H4R3me1 at HMGB2 promoter and HMGB2 binding at ACSL1 promoter, ferroptosis assays, lipid peroxidation measurement\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for transcriptional cascade + genetic gain/loss-of-function + functional ferroptosis assay, single lab\",\n      \"pmids\": [\"38376246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ergosterol directly binds to ACSL1, targeting a drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) and stabilizing the closed conformation of ACSL1's C-terminal domain, allosterically maintaining enzymatic activity. Ergosterol is enriched in mitochondria and promotes fatty acid β-oxidation through this ACSL1 allosteric activation mechanism.\",\n      \"method\": \"In vitro binding/structural studies (conformational change analysis), structure-activity relationship analysis of sterols vs ACSL1 and SCAP, cellular fatty acid β-oxidation assays, mitochondrial enrichment assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct binding and conformational change data with functional FAO readout, but structural details limited by abstract description; single lab\",\n      \"pmids\": [\"39799570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Parkinson's disease microglia, activated TBK1 promotes ACSL1 enrichment on the ER (opposite to its hepatic fasting role), where ACSL1 generates acyl-CoA channeled into lipid droplet biogenesis. ACSL1 overexpression also promotes TBK1 K63-ubiquitination via Nrdp1, creating a feedforward loop. NF-κB directly binds the ACSL1 promoter to drive transcription in microglia.\",\n      \"method\": \"Single-nucleus RNA-seq, gain/loss-of-function experiments, TBK1 activation studies, Nrdp1 ubiquitination assay, ChIP for NF-κB at ACSL1 promoter, lipid droplet quantification, dopaminergic neuron death assay\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (ubiquitination, ChIP, localization, functional) in a single study, single lab\",\n      \"pmids\": [\"40684214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Impaired hepatic ketogenesis (via HMGCS2 loss) causes excess acetyl-CoA accumulation that drives ACSL1 translocation to the ER, where ACSL1-mediated fatty acid re-esterification promotes hepatic steatosis. L-carnitine, which buffers acetyl-CoA, reduces ER-associated ACSL1 and alleviates steatosis.\",\n      \"method\": \"Liver-specific HMGCS2 knockout mice, Western blot for ACSL1 subcellular fractionation (ER vs mitochondria), L-carnitine rescue experiment, human primary hepatocytes, histologic analysis of human MASH samples\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO + subcellular fractionation + pharmacological rescue + human tissue validation, single lab but multiple approaches\",\n      \"pmids\": [\"40692014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FATP2 (SLC27A2) physically interacts with ACSL1 in non-small cell lung cancer cells, as shown by Co-IP. Co-transfection of si-FATP2 with pcDNA-ACSL1 further inhibited proliferation and lipid deposition and promoted fatty acid decomposition, indicating FATP2 regulates lipid metabolism through ACSL1.\",\n      \"method\": \"Co-immunoprecipitation (FATP2–ACSL1 interaction), siRNA knockdown of FATP2, ACSL1 overexpression, cell proliferation and lipid deposition assays\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, functional assays without deep mechanistic characterization, single lab\",\n      \"pmids\": [\"37172427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACSL1 knockdown in neonatal mouse cardiomyocytes and via AAV9 in adult mice promoted cell cycle progression from G0 to G2 phase, enhanced myocardial regeneration, and improved cardiac function after MI, associated with AKT activation and FOXO1 nuclear exclusion.\",\n      \"method\": \"AAV9-mediated ACSL1 knockdown in mice, primary cardiomyocyte culture, cell cycle analysis, AKT/FOXO1 pathway Western blot, cardiac function assessment (echocardiography), myocardial infarction model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV knockdown + in vitro cell cycle mechanistic data + defined signaling pathway, single lab\",\n      \"pmids\": [\"35122795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACSL1 inhibition (triacsin C) or knockdown suppressed acetate-plus-TNFα-synergized MCP-1 production in monocytes through the ACSL1/MAPK/NF-κB axis; ACSL1 inhibition reduced p38 MAPK, ERK1/2, and NF-κB phosphorylation and NF-κB/AP-1 activity. Neither CPT-I nor SPT inhibition recapitulated this effect, placing acyl-CoA formation specifically upstream.\",\n      \"method\": \"Pharmacological ACSL1 inhibition, siRNA knockdown in THP-1 monocytes, ELISA, qRT-PCR, Western blot for MAPK/NF-κB pathway phosphorylation, NF-κB/AP-1 reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent pharmacological/genetic approaches with mechanistic pathway epistasis, single lab\",\n      \"pmids\": [\"34299302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACSL1 is a long-chain acyl-CoA synthetase that activates free fatty acids (preferring C10–C18 substrates including linoleate) to acyl-CoA thioesters; its subcellular localization—dynamically regulated at mitochondria vs. ER by scaffolding interactions with TBK1 or sortilin, and by the cellular acetyl-CoA pool—determines whether acyl-CoAs are channeled toward β-oxidation or lipid re-esterification/droplet biogenesis. At mitochondria, ACSL1 interacts with CPT1b (via its N-terminal 100 aa) and with MCL-1 (via a non-canonical BH3-domain) to support long-chain FAO; at the ER it promotes re-esterification and lipid droplet formation. ACSL1 also drives ferroptosis by incorporating polyunsaturated fatty acids into triacylglycerols for lipid peroxidation, mediates protein N-myristoylation, and acts upstream of NF-κB/MAPK inflammatory signaling in monocytes; its transcription is controlled by SREBP2 (via SRE), CHREBP (high glucose), NF-κB (LPS), and epigenetic regulators including PRMT1/H4R3me2a and the PRMT7/HMGB2 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACSL1 is a long-chain acyl-CoA synthetase that activates free fatty acids (C10–C18 saturated, plus palmitoleate, oleate, and linoleate) to acyl-CoA thioesters, the committed first step that channels fatty acids into oxidative and biosynthetic fates [#0]. Its enzymatic activity requires all five structural regions of the protein and can be allosterically tuned by direct sterol binding to a pocket in its acetyl-CoA synthetase-like domain [#0, #24], and it also thioesterifies xenobiotic 2-arylpropionic acid NSAIDs with stereoselectivity, mediating their chiral inversion [#1]. The central organizing principle of ACSL1 biology is that its subcellular partitioning between mitochondria and ER dictates metabolic outcome: mitochondrial scaffolding by unphosphorylated TBK1 and by an interaction of its N-terminal 100 residues with CPT1b localizes ACSL1 to the outer mitochondrial membrane to drive β-oxidation, whereas loss of this scaffolding, sortilin-mediated endolysosomal degradation, or acetyl-CoA accumulation redirects ACSL1 to the ER toward fatty acid re-esterification, lipid droplet biogenesis, and hepatic steatosis [#6, #8, #12, #26]. MCL-1 binds ACSL1 through a non-canonical BH3 interaction with its anti-apoptotic groove and is specifically required for long-chain FAO [#11]. By trapping fatty acids as acyl-CoAs, ACSL1 promotes cellular fatty acid uptake and supplies AMP that activates AMPK signaling [#3, #5]. ACSL1 channels linoleate into ω-O-acylceramide synthesis essential for the skin barrier, and its genetic loss causes embryonic lethality and barrier defects in mice [#13]. Through incorporation of polyunsaturated fatty acids into triacylglycerols it drives lipid peroxidation and ferroptosis [#7], while in cancer cells its production of myristoyl-CoA supports protein N-myristoylation that stabilizes FSP1 and confers ferroptosis resistance [#14, #15]. In monocytes and macrophages ACSL1 acts upstream of MAPK/NF-κB inflammatory signaling independently of β-oxidation or ceramide synthesis [#16, #29]. ACSL1 transcription is controlled by SREBP2 via a sterol regulatory element, by FXR, CHREBP, and NF-κB, and by epigenetic regulators including PRMT1-controlled H4R3 methylation at its promoter [#9, #10, #19, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established ACSL1 as a bona fide long-chain acyl-CoA synthetase with defined substrate preference and a multi-region structural requirement for catalysis, answering what reaction the enzyme performs.\",\n      \"evidence\": \"Purified recombinant rat enzyme, in vitro activity assays, and deletion mutagenesis of five structural regions\",\n      \"pmids\": [\"8973631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve subcellular targeting or physiological substrate channeling\", \"No high-resolution structure of the catalytic mechanism\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended ACSL1 substrate scope to xenobiotics, showing it stereoselectively thioesterifies 2-arylpropionic NSAIDs and mediates their chiral inversion in liver.\",\n      \"evidence\": \"Purified recombinant enzyme with Michaelis-Menten kinetics on R/S enantiomers\",\n      \"pmids\": [\"10725307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro only; physiological contribution in vivo not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked ACSL1 localization to function, showing mitochondrial ACSL1 drives fatty acid uptake by metabolic trapping rather than acting as a plasma-membrane transporter.\",\n      \"evidence\": \"Confocal imaging, subcellular fractionation, and radiolabeled/fluorescent FA uptake assays in hepatoma cells and adipocytes\",\n      \"pmids\": [\"22022213\", \"23024797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression, which may bias localization\", \"Did not address what controls mitochondrial vs ER targeting\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed ACSL1 enzymatic activity upstream of AMPK activation, connecting fatty acid activation to energy-sensing signaling.\",\n      \"evidence\": \"siRNA knockdown in adipocytes with AMP/ATP and AMPK phosphorylation readouts\",\n      \"pmids\": [\"20667975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking acyl-CoA synthesis to AMP generation not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified direct transcriptional control of ACSL1 by SREBP2 through a sterol regulatory element, tying ACSL1 expression to cholesterol/lipid homeostasis.\",\n      \"evidence\": \"Promoter reporter with SRE mutagenesis, DNA-binding assay, SREBP2 knockdown, and in vivo statin models in two species\",\n      \"pmids\": [\"26728456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Restricted to the C-promoter transcript variant\", \"Did not address other promoter elements\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed hepatic ACSL1 is required for bile acid biosynthesis and is itself an FXR target, embedding it in a feedback loop with sterol/bile acid metabolism.\",\n      \"evidence\": \"Adenoviral ACSL1 knockdown in mice, genome-wide expression, bile acid quantification, and FXR-KO with agonist treatment\",\n      \"pmids\": [\"30580099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACSL1 acts directly in bile acid synthesis or indirectly via SREBP2 not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a metabolism-independent role for ACSL1 upstream of NF-κB in inflammatory activation of monocytes.\",\n      \"evidence\": \"Triacsin C inhibition and siRNA in THP-1/primary monocytes with NF-κB and inflammatory marker readouts; β-oxidation and ceramide inhibition as controls\",\n      \"pmids\": [\"30845379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The acyl-CoA species or lipid signal driving NF-κB not identified\", \"Direct molecular link between acyl-CoA and NF-κB unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the scaffolding paradigm: unphosphorylated TBK1 anchors ACSL1 at mitochondria to favor β-oxidation, with loss of scaffolding shifting ACSL1 to the ER and re-esterification.\",\n      \"evidence\": \"Liver-specific TBK1 KO, Co-IP, fractionation, 13C tracing, and kinase-dead rescue\",\n      \"pmids\": [\"33152322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TBK1–ACSL1 interaction not resolved\", \"How fasting state controls TBK1 phosphorylation/ACSL1 binding incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected ACSL1 to protein N-myristoylation, revealing a non-classical output of its acyl-CoA synthesis in driving cancer metastasis.\",\n      \"evidence\": \"Proteomics, gain/loss-of-function, lipidomics, myristoylation assay, AMPK/Src readouts in ovarian cancer cells\",\n      \"pmids\": [\"33082557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific myristoylated substrates beyond pathway-level readouts limited at this stage\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ACSL1 as a driver of ferroptosis by incorporating PUFAs into triacylglycerols that fuel lipid peroxidation, distinguishing this from GPX4-axis ferroptosis.\",\n      \"evidence\": \"Genetic loss-of-function, lipidomics, lipid peroxidation assays, and TG-biosynthesis pharmacologic epistasis across cell types and a tumor model\",\n      \"pmids\": [\"33854057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TG-stored PUFAs are mobilized for peroxidation not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the N-terminal 100 residues as the CPT1b-binding mitochondrial targeting determinant required for ACSL1-supported FAO.\",\n      \"evidence\": \"N-terminal deletion mutagenesis, Co-IP with CPT1b, confocal localization, and Seahorse FAO assays in C2C12 myotubes\",\n      \"pmids\": [\"34511469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CPT1b binding is required in tissues other than muscle unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated ACSL1 is essential for ω-O-acylceramide synthesis and the skin barrier by activating linoleate, explaining its requirement for viability.\",\n      \"evidence\": \"Systemic Acsl1 KO mice with ceramide/TG lipidomics and epidermal immunofluorescence\",\n      \"pmids\": [\"34813948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of barrier defect vs other functions to embryonic lethality not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ACSL1 as a brake on cardiomyocyte cell-cycle re-entry, linking its loss to myocardial regeneration via AKT/FOXO1.\",\n      \"evidence\": \"AAV9 knockdown in mice, cell-cycle analysis, AKT/FOXO1 Western blot, and post-MI cardiac function assessment\",\n      \"pmids\": [\"35122795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Metabolic vs signaling basis of the cell-cycle effect not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the inflammatory role of ACSL1 to MMP-9 and macrophage foaming, defining JNK/ERK/NF-κB and CD36-FABP4-p38-PPARδ axes downstream.\",\n      \"evidence\": \"Triacsin C and siRNA in monocytes with pathway phosphorylation, reporter assays, and in vivo oral inhibitor in high-fat-fed mice\",\n      \"pmids\": [\"37658104\", \"37416456\", \"34299302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct acyl-CoA-derived signal initiating MAPK/NF-κB not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified FSP1 as a myristoylation substrate stabilized by ACSL1, explaining how ACSL1 can confer ferroptosis resistance in addition to driving it.\",\n      \"evidence\": \"ACSL1 gain/loss-of-function with FSP1 stability, localization, and N-myristoylation assays in ovarian cancer cells\",\n      \"pmids\": [\"36882396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of pro- vs anti-ferroptotic ACSL1 roles context-dependent and not unified mechanistically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the transcriptional control of ACSL1 to glucose (CHREBP) and inflammatory (NF-κB) inputs and additional oncogenic coactivators.\",\n      \"evidence\": \"ChIP and reporter assays for CHREBP/p65 in BMDMs; ChIP for HBXIP/Sp1 at the ACSL1 promoter in breast cancer cells\",\n      \"pmids\": [\"36054206\", \"28132807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial regulation by these factors under physiological conditions not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed MCL-1 as a direct ACSL1 partner via a non-canonical BH3 interaction selectively required for long-chain FAO, coupling an anti-apoptotic protein to mitochondrial metabolism.\",\n      \"evidence\": \"Reciprocal Co-IP, BH3 mutagenesis, Mcl1 conditional KO, BH3-mimetic inhibitors, and Seahorse FAO across cells and tissues\",\n      \"pmids\": [\"38503284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of how the BH3 interaction promotes FAO not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined sortilin-mediated endolysosomal degradation as a route controlling mitochondrial ACSL1 abundance and systemic metabolic phenotype.\",\n      \"evidence\": \"Sort1 KO/knockdown in adipocytes and mice, fractionation, co-localization, AMPK/PGC1α assays, and HFD metabolic phenotyping\",\n      \"pmids\": [\"39232011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering sortilin-dependent ACSL1 trafficking unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added epigenetic and PRMT-axis control of ACSL1 transcription that tunes ferroptosis sensitivity across disease contexts.\",\n      \"evidence\": \"PRMT1 inhibitor/KO with H4R3me2a ChIP-seq and ACSL1-KO epistasis in AML; PRMT6/STAT1 in diabetic nephropathy; PRMT7/HMGB2 ChIP cascade in pancreatitis\",\n      \"pmids\": [\"37144835\", \"39134684\", \"38376246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these PRMT axes converge on shared promoter elements not established\", \"Mostly single-lab, disease-specific observations\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a structural-allosteric mechanism, showing ergosterol binds an ASLD1 pocket to stabilize ACSL1's closed conformation and sustain activity and mitochondrial FAO.\",\n      \"evidence\": \"In vitro binding/conformational analysis, sterol structure-activity relationships, and cellular FAO assays\",\n      \"pmids\": [\"39799570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution structure of the binding pocket limited\", \"Physiological sterol ligand in mammalian cells not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed metabolic state controls ACSL1 ER-targeting: acetyl-CoA accumulation (from impaired ketogenesis) and microglial TBK1 activation redirect ACSL1 to the ER for re-esterification and lipid droplet biogenesis in disease.\",\n      \"evidence\": \"HMGCS2-KO mice with fractionation and L-carnitine rescue and human MASH samples; snRNA-seq, Nrdp1 ubiquitination, NF-κB ChIP, and lipid droplet assays in PD microglia\",\n      \"pmids\": [\"40692014\", \"40684214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How acetyl-CoA and TBK1 phosphorylation state mechanistically converge on ACSL1 trafficking not unified\", \"Single-lab disease models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular switch that integrates scaffolding (TBK1, CPT1b, MCL-1), degradation (sortilin), metabolite sensing (acetyl-CoA, sterols), and post-translational state to set ACSL1's mitochondria-vs-ER partitioning remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model or structure of the targeting determinants\", \"How a single enzyme is partitioned in real time between competing organelles is unknown\"]\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, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 6, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 25, 26]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 17, 18, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TBK1\", \"CPT1B\", \"MCL1\", \"SORT1\", \"SLC27A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}