Affinage

ACSL3

Fatty acid CoA ligase Acsl3 · UniProt O95573

Length
720 aa
Mass
80.4 kDa
Annotated
2026-06-09
56 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACSL3 is a long-chain acyl-CoA synthetase that activates fatty acids and channels them into distinct lipid pools, thereby governing lipid droplet biogenesis, membrane phospholipid composition, fatty acid oxidation versus storage decisions, and downstream cell-fate outcomes (PMID:17761945, PMID:36192773, PMID:41564380). Through its enzymatic activity it partitions activated fatty acids into β-oxidation rather than triglyceride synthesis (PMID:17761945), drives accumulation of lipid droplets from exogenous fatty acids (PMID:36192773), and routes arachidonic acid into phosphatidylinositols to supply the LPIAT1-dependent prostaglandin pathway (PMID:32034305). By shaping the monounsaturated-to-polyunsaturated phospholipid ratio it acts as a central determinant of ferroptosis susceptibility, with its enzymatic activity directly enhanced by vitamin A/ATRA to suppress lipid peroxidation (PMID:41909752). ACSL3 also performs catalytic-activity-independent functions: it binds the open conformation of Lyn kinase to mediate its Golgi export to the plasma membrane (PMID:20605918) and is required for formation of fusion-competent autophagosomal membranes during starvation (PMID:40728409, PMID:41346954). ACSL3 abundance is tightly set post-translationally by competing degradation and stabilization machinery — ubiquitin E3 ligases TRIM25, NEDD4, and HRD1 promote its turnover (PMID:39285846, PMID:39743027, PMID:41130543), whereas SUMO2 and NT5DC2 block its ubiquitination to stabilize it (PMID:40526170, PMID:41974665) — and transcriptionally by LXR, MEF2D, and PPARγ together with m6A- and splicing-dependent control of its mRNA (PMID:20219900, PMID:39744125, PMID:41933714, PMID:39160584, PMID:41037014). As a hub linking fatty acid metabolism to cell survival, ACSL3 determines hepatocyte susceptibility to palmitate lipotoxicity (PMID:41564380) and modulates tumor growth, immune infiltration, and therapy resistance across multiple cancers (PMID:36192773, PMID:33127675, PMID:40059153).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2007 High

    Established that ACSL3 is a regulated node controlling whether activated fatty acids enter oxidation or storage, defining its metabolic decision-making role.

    Evidence Transcriptional reporter, siRNA knockdown, and fatty acid oxidation/acyl-CoA synthetase assays in HepG2 cells and a hamster model under Oncostatin M stimulation

    PMID:17761945

    Open questions at the time
    • Did not resolve which lipid species are preferentially generated
    • Mechanism by which ACSL3 activity biases toward β-oxidation not defined
  2. 2010 High

    Revealed that ACSL3 has a catalytic-activity-independent function in protein trafficking, distinct from its enzymatic role.

    Evidence Co-IP, conformation-dependent binding assays, domain-deletion mutants lacking the LR2 catalytic domain, and live-cell trafficking imaging of Lyn kinase Golgi export

    PMID:20605918

    Open questions at the time
    • Structural basis of ACSL3-Lyn interaction not solved
    • Whether ACSL3 traffics other kinases unknown
  3. 2010 High

    Identified direct transcriptional control of ACSL3 by LXR, linking nuclear lipid sensing to ACSL3-dependent fatty acid uptake.

    Evidence Promoter reporter assays with LXR response element mapping, siRNA knockdown, and acyl-CoA synthetase/fatty acid uptake assays in placental trophoblasts

    PMID:20219900

    Open questions at the time
    • Tissue-specificity of LXR regulation not addressed
    • Interplay with other transcriptional inputs unexplored
  4. 2017 High

    Localized ACSL3 function to insulin secretory granules and showed substrate selectivity toward arachidonate, connecting it to regulated secretion.

    Evidence Subcellular fractionation, stable shRNA knockdown, glucose-stimulated insulin secretion in INS-1 cells and human islets, and phospholipid profiling

    PMID:28193492

    Open questions at the time
    • Molecular link between acyl-CoA synthesis and secretion not defined
    • Whether granule targeting requires specific partners unknown
  5. 2018 Medium

    Defined ACSL3's distinct subcellular itinerary (trans-Golgi/endosomes and lipid droplets), separating it spatially from the ER-resident ACSL4.

    Evidence Subcellular fractionation, confocal immunofluorescence, and tumor array immunohistochemistry in fibrosarcoma and breast cancer cells

    PMID:29450800

    Open questions at the time
    • Targeting determinants for Golgi/LD localization not mapped
    • Functional consequence of compartment-specific localization not tested
  6. 2020 High

    Showed ACSL3 supplies arachidonate-derived phosphatidylinositols to an LPIAT1 axis sustaining prostaglandin synthesis, a tumor-promoting lipid signaling output.

    Evidence ACSL3/LPIAT1 knockdown in lung cancer lines and KrasG12D mice, lipidomics, prostaglandin measurement, and in vivo tumorigenesis assays

    PMID:32034305

    Open questions at the time
    • Direct enzymatic flux of arachidonate through ACSL3 to PI not isotopically traced
    • Generalizability beyond lung cancer not established
  7. 2020 High

    Connected ACSL3 to autophagy machinery via direct binding to GABARAPL2 and ER recruitment of the UFM1 conjugation system.

    Evidence CRISPR endogenous ATG8 tagging, affinity purification-MS interactome, Co-IP, and knockdown of ufmylation/ER-phagy components

    PMID:32843575

    Open questions at the time
    • Whether ACSL3 LIR-mediated binding requires lipid catalysis unclear
    • Physiological role of ACSL3-UFM1 link in vivo not tested
  8. 2020 High

    Demonstrated ACSL3 dependence for lipid droplet accumulation from exogenous fatty acids and identified its role in shaping ferroptosis susceptibility in cancer.

    Evidence Genetic/pharmacologic ACSL3 inhibition, isotope-tracing lipidomics, orthotopic ccRCC mouse model, and FACS ferroptosis assays

    PMID:36192773

    Open questions at the time
    • Lipid species mediating ferroptosis modulation not fully resolved
    • Dependence on fatty acid composition mechanistically incomplete
  9. 2020 High

    Established an ACSL3-PAI-1 axis by which ACSL3 reshapes the tumor immune microenvironment in pancreatic cancer.

    Evidence Acsl3 genetic KO in mouse PDAC, in vivo tumor growth, immune infiltrate flow cytometry, and PAI-1 measurement/inhibition with therapy response

    PMID:33127675

    Open questions at the time
    • How ACSL3 metabolic activity controls PAI-1 secretion is unclear
    • Whether the effect is fully lipid-dependent untested
  10. 2021 Medium

    Placed ACSL3 within a Rab18-PLIN2 lipid droplet complex regulating triacylglycerol levels and LD dynamics.

    Evidence Co-IP, Rab18 overexpression/knockdown, lipid droplet staining, and TAG quantification in C2C12 myoblasts

    PMID:33713834

    Open questions at the time
    • Single primary binding method without reciprocal structural validation
    • Direct vs indirect nature of complex assembly unresolved
  11. 2024 High

    Resolved post-translational control of ACSL3 stability, showing E3 ligase TRIM25 (recruited by ANKRD1) drives K63-ubiquitination and degradation to amplify ferroptosis.

    Evidence IP-MS, reciprocal Co-IP, proximity ligation, K63-linkage ubiquitination assays, and in vivo rAAV9 knockdown in renal ischemia-reperfusion

    PMID:39285846

    Open questions at the time
    • Whether K63-ubiquitination targets ACSL3 to proteasome or another fate unclear
    • Other adaptors recruiting TRIM25 to ACSL3 unknown
  12. 2025 High

    Expanded the ACSL3 degradation network to NEDD4 (via TNFAIP3) and HRD1, defining multiple converging ubiquitin pathways that tune ACSL3 levels in disease.

    Evidence Co-IP, ubiquitination assays identifying E3 ligases, and in vivo AAV knockdown in TBI and ethanol-diet liver injury models

    PMID:39743027 PMID:41130543

    Open questions at the time
    • Relative contribution of each E3 ligase across tissues not compared
    • Ubiquitination sites on ACSL3 not mapped
  13. 2025 Medium

    Identified stabilizing factors SUMO2 and NT5DC2 that block ACSL3 ubiquitination, establishing a balance between degradation and protection that sets ferroptosis sensitivity.

    Evidence Co-IP, ubiquitination assays, and ACSL3 rescue/knockdown ferroptosis experiments in hepatocellular and bladder cancer cells

    PMID:40526170 PMID:41974665

    Open questions at the time
    • Whether SUMO2 acts via direct SUMOylation of ACSL3 not resolved
    • Single-lab Co-IP evidence per partner without structural validation
  14. 2025 High

    Demonstrated that ACSL3 enzymatic activity directly governs the MUFA/PUFA phospholipid ratio and can be pharmacologically enhanced (vitamin A/ATRA) to suppress ferroptosis and extend lifespan.

    Evidence In vitro enzymatic activity/binding assays, phospholipid lipidomics, ferroptosis assays, and ACSL3-dependent C. elegans lifespan analysis

    PMID:41909752

    Open questions at the time
    • Structural basis of vitamin A binding to ACSL3 not solved
    • Mammalian lifespan/healthspan effects not tested
  15. 2025 High

    Refined ACSL3's catalytic-activity-independent role in autophagy to an early step of fusion-competent autophagosomal membrane formation, regulated by SYNTAXIN17.

    Evidence Knockdown/overexpression with enzymatic-dead mutants, WIPI2/LC3/FIP200 imaging, LC3 lipidation assays, and SYNTAXIN17 epistasis

    PMID:40728409 PMID:41346954

    Open questions at the time
    • Molecular mechanism by which ACSL3 confers membrane fusion competence unknown
    • How ACSL3 partitions between LD biogenesis and autophagosome roles unclear
  16. 2026 High

    Positioned ACSL3 as a central genome-wide determinant of hepatocyte palmitate lipotoxicity, integrating its substrate routing into a tractable therapeutic node.

    Evidence Genome-wide CRISPR screen with genetic/pharmacologic validation, isotope tracing of fatty acid incorporation, and human MASLD tissue with spatial transcriptomics

    PMID:41564380

    Open questions at the time
    • Whether catalytic vs non-catalytic functions drive lipotoxicity not dissected
    • Long-term consequences of ACSL3 inhibition in liver not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ACSL3 mechanistically toggles between its catalytic functions (fatty acid activation, phospholipid remodeling, ferroptosis control) and its catalytic-activity-independent functions (Lyn export, autophagosome membrane formation) within a single protein remains unresolved.
  • No structural model coupling catalytic and scaffolding activities
  • Determinants directing ACSL3 to Golgi vs lipid droplet vs autophagosomal membranes unknown
  • Ubiquitination/SUMOylation site mapping incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005811 lipid droplet 3 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005768 endosome 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3
Partners
ANKRD1GABARAPL2LYNNT5DC2PLIN2RAB18TRIM25YES1
Complex memberships
Rab18-PLIN2-ACSL3 lipid droplet complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 ACSL3 associates with the C-lobe of the Lyn kinase domain on the Golgi in a conformation-dependent manner (open conformation of Lyn required) and mediates Golgi export of Lyn to the plasma membrane; an ACSL3 mutant lacking the LR2 catalytic domain retains both Lyn-binding and Golgi export activity, indicating the function is independent of ACSL3 enzymatic activity. Co-immunoprecipitation, overexpression and siRNA knockdown of ACSL3 with live-cell trafficking assays, domain-deletion mutagenesis, confocal imaging Journal of cell science High 20605918
2007 Oncostatin M activates transcription of ACSL3 (and ACSL5) in hepatocytes through the ERK signaling pathway; increased ACSL3 activity partitions fatty acids into β-oxidation rather than triglyceride synthesis, reducing TG accumulation; siRNA knockdown of ACSL3/ACSL5 abrogates OM-enhanced fatty acid oxidation. Transcriptional reporter assays, siRNA knockdown, fatty acid oxidation assays in HepG2 cells and in vivo hamster model, acyl-CoA synthetase activity measurement Arteriosclerosis, thrombosis, and vascular biology High 17761945
2010 LXR activation directly regulates ACSL3 transcription through a conserved LXR response element in the ACSL3 promoter in human placental trophoblast cells, increasing acyl-CoA synthetase activity and fatty acid uptake; ACSL3 silencing attenuates LXR-mediated increases in acyl-CoA synthetase activity. Promoter reporter assays with LXR response element identification, siRNA knockdown, acyl-CoA synthetase activity assay, fatty acid uptake assay Journal of lipid research High 20219900
2011 ACSL3 expression is induced by ER stress (tunicamycin) in hepatocytes; ACSL3 shRNA (but not ACSL1 shRNA) blocks ER stress-induced lipid accumulation; GSK-3β acts upstream of ACSL3 in this pathway, as GSK-3β inhibitors or shRNA suppress ACSL3 upregulation and lipid accumulation. shRNA knockdown, GSK-3β inhibitor treatment, lipid accumulation assays (Oil Red O), western blot in HuH-7 and HepG2 cells, hepatitis B virus mutant large surface protein model Journal of cellular biochemistry Medium 21328461
2013 ACSL3 mediates palmitic acid (PA)-induced osteoblastic differentiation and calcium deposition in vascular smooth muscle cells; ACS inhibitor or ACSL3 siRNA prevents PA-induced BMP-2 and Msx2 expression and calcium deposition; adenovirus-mediated ACSL3 overexpression enhances these effects; EPA inhibits ACSL3 expression and downstream osteoblastic gene induction. siRNA knockdown, adenovirus-mediated overexpression, ACS pharmacological inhibitor, qPCR for osteoblastic markers, calcium deposition assay, immunohistochemistry of human plaques PloS one High 23840832
2017 ACSL3 overexpression in androgen-dependent LNCaP prostate cancer cells upregulates AKR1C3 (involved in steroidogenesis converting DHEAS to testosterone) and downregulates the androgen-inactivating enzyme UGT2B, promoting intratumoral androgen synthesis and cell proliferation in response to DHEAS. ACSL3 overexpression in LNCaP cells, gene expression profiling, testosterone measurement by mass spectrometry, cell proliferation assays Cancer science Medium 28771887
2017 ACSL3 and ACSL4 are concentrated in insulin secretory granules of pancreatic beta cells; shRNA-mediated knockdown of ACSL3 or ACSL4 inhibits glucose-stimulated insulin secretion ~50% in INS-1 832/13 cells and in human pancreatic islets; ACSL3 knockdown preferentially reduces arachidonate over palmitate as substrate. Subcellular fractionation, immunostaining, stable shRNA knockdown cell lines, glucose-stimulated insulin secretion assay, ACSL enzyme activity assay, phospholipid profiling Archives of biochemistry and biophysics High 28193492
2018 Upper small intestinal ACSL3 expression is required for fatty acid-dependent pre-absorptive signaling that regulates glucose homeostasis; high-fat feeding reduces ACSL3 expression and impairs fatty acid sensing; restoration of Lactobacillus gasseri increases ACSL3 expression and restores fatty acid sensing and glucose tolerance in rodents. Upper small intestinal infusion of lipids, surgical duodenal cannulation, in vivo glucose clamps, ACSL3 knockdown/expression measurements, microbiota transplantation, L. gasseri probiotic administration Cell metabolism High 29514066
2018 Endogenous ACSL3 in fibrosarcoma and breast cancer cells localizes to the trans-Golgi network/endosomal compartments, distinct from ACSL4 which follows the endoplasmic reticulum pattern; both isoforms associate with lipid droplets. Subcellular fractionation, confocal immunofluorescence imaging, immunohistochemistry of tumor arrays Molecular and cellular biochemistry Medium 29450800
2020 ACSL3 channels arachidonic acid (AA) into phosphatidylinositols, providing a substrate pool for LPIAT1 to sustain elevated prostaglandin synthesis in non-small cell lung cancer; LPIAT1 knockdown suppresses proliferation and in vivo tumorigenesis, defining an ACSL3-LPIAT1 axis for prostaglandin production. ACSL3 and LPIAT1 knockdown in lung cancer cell lines and KrasG12D mouse models, lipidomics, prostaglandin measurement, proliferation and anchorage-independent growth assays, in vivo tumorigenesis Oncogene High 32034305
2020 ACSL3 is required for lipid droplet accumulation from exogenous serum-derived fatty acids (not de novo lipogenesis) in clear cell renal cell carcinoma cells; genetic or pharmacologic ACSL3 suppression is cytotoxic to ccRCC in vitro and reduces tumor weight in an orthotopic mouse model; ACSL3 inhibition decreases ferroptosis susceptibility in a manner dependent on exogenous fatty acid composition. siRNA/shRNA knockdown, pharmacological inhibition, isotope-tracing lipidomics, Oil Red O staining, cell viability assays, orthotopic mouse tumor model, FACS-based ferroptosis assays Cancer & metabolism High 36192773
2020 ACSL3 is a direct binding partner of GABARAPL2 (via LC3-interacting regions); through this interaction GABARAPL2 is recruited to the ER, anchoring UBA5 (UFM1-activating enzyme) at the ER; ACSL3 depletion and lipid droplet induction affect abundance of ufmylation components and ER-phagy, establishing ACSL3 as a regulator of the UFM1 conjugation pathway. CRISPR/Cas9 endogenous tagging of ATG8 proteins, interaction proteomics (affinity purification–mass spectrometry), co-immunoprecipitation, knockdown experiments Journal of cell science High 32843575
2020 ACSL3 knockout in pancreatic ductal adenocarcinoma hinders tumor progression, reduces tumor fibrosis, reduces immunosuppressive cell infiltration, and increases cytotoxic T cell infiltration; this is mediated at least in part through decreased PAI-1 secretion from tumor cells, defining an ACSL3–PAI-1 signaling axis. Acsl3 genetic knockout in mouse PDAC models, in vivo tumor growth assays, flow cytometry of tumor-infiltrating immune cells, PAI-1 measurement, PAI-1 pharmacological inhibition with chemo/immunotherapy response assays Science advances High 33127675
2021 Rab18 interacts with ACSL3 on lipid droplets and promotes ACSL3 LD localization; Rab18 also binds PLIN2, which recruits Rab18 from ER to LDs; the Rab18-PLIN2-ACSL3 complex regulates triacylglycerol levels and lipid droplet dynamics in myoblast cells. Co-immunoprecipitation, Rab18 overexpression and knockdown, lipid droplet staining, TAG quantification, confocal imaging in C2C12 cells Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 33713834
2022 MAT2A mediates ferroptosis resistance in gastric cancer by producing S-adenosylmethionine (SAM), which upregulates ACSL3 expression via H3K4me3 trimethylation at the ACSL3 promoter, thereby increasing resistance to ferroptosis. Pharmacological and genetic blockade of methionine cycle, chromatin immunoprecipitation (H3K4me3 at ACSL3 promoter), gene expression analysis, in vitro and in vivo ferroptosis assays Free radical biology & medicine Medium 35182729
2023 BRD4 controls the splicing efficiency of ACSL3 pre-mRNA by recruiting SRPK2 to assemble a splicing catalytic platform; the AMP-binding domain of ACSL3 influences arachidonic acid synthesis and thus determines susceptibility to erastin-induced ferroptosis in osteosarcoma cells. BRD4 inhibition (in vitro and in vivo), SRPK2 co-IP, RT-PCR splicing analysis, ACSL3 domain mutants, arachidonic acid measurement, ferroptosis assays Cell death & disease Medium 37993451
2023 FTO demethylates m6A modifications on ACSL3 mRNA (and GPX4 mRNA), decreasing their stability and expression, thereby sensitizing oral squamous cell carcinoma cells to ferroptosis in vitro and in vivo. FTO overexpression/knockdown, m6A methylation analysis (MeRIP), mRNA stability assays, ferroptosis assays (lipid ROS, cell viability) in vitro and in vivo International journal of molecular sciences Medium 38003537
2024 ANKRD1 directly binds ACSL3 and promotes its degradation via K63-linked ubiquitination catalyzed by the E3 ligase TRIM25, reducing ACSL3 protein levels, amplifying lipid peroxidation and ferroptosis, and exacerbating renal ischemia-reperfusion injury. Immunoprecipitation-mass spectrometry to identify ANKRD1 interactors, Co-IP and proximity ligation assay for ANKRD1-ACSL3 and TRIM25-ACSL3 interactions, ubiquitination assays (K63-linkage), ANKRD1 knockdown (rAAV9) in vivo, siRNA in vitro, cell viability and lipid peroxidation assays Clinical and translational medicine High 39285846
2024 MEF2D directly binds the promoter region of ACSL3 and transcriptionally upregulates ACSL3 expression, inhibiting ferroptosis and enhancing sorafenib resistance in hepatocellular carcinoma. Promoter binding assays (ChIP or EMSA), gene expression analysis, ACSL3 silencing in sorafenib-resistant HCC cells, ferroptosis level assessment Frontiers in pharmacology Medium 39744125
2024 METTL3 in cancer-associated fibroblast-derived exosomes induces m6A modification on ACSL3 mRNA, stabilizing ACSL3 expression, which promotes colorectal cancer cell proliferation, metastasis, and suppresses ferroptosis; METTL3 knockdown in CAFs reverses these effects and is rescued by ACSL3 overexpression. Methylated RNA immunoprecipitation (MeRIP), dual-luciferase reporter assay, exosome isolation, METTL3 knockdown in CAFs, ACSL3 overexpression rescue, in vitro and in vivo tumor models Biology direct Medium 39160584
2024 ACSL3 interacts with YES1 (Src-family kinase) and suppresses its activation (phospho-Tyr419), consequently inhibiting YAP1 nuclear colocalization and transcriptional complex formation in breast cancer cells; ACSL3 knockdown promotes cell proliferation, migration, and EMT. Co-immunoprecipitation for ACSL3-YES1 interaction, phospho-YES1 measurement, ACSL3 knockdown/overexpression, YAP1 nuclear localization assay, in vitro and in vivo functional assays Cancer biology & medicine Medium 38953696
2025 TNFAIP3 promotes ACSL3 degradation via NEDD4-mediated ubiquitination, reducing ACSL3 levels, enhancing lipid peroxidation and ferroptosis in neurons after traumatic brain injury; TNFAIP3 overexpression increases neuronal cell death, while TNFAIP3 knockdown (AAV-shTNFAIP3) alleviates ferroptosis and cognitive impairment. Co-IP for TNFAIP3-ACSL3 interaction, ubiquitination assay with NEDD4, TNFAIP3 overexpression/knockdown, AAV-shTNFAIP3 in mouse TBI model, lipid peroxidation and ferroptosis markers Free radical biology & medicine Medium 39743027
2025 HRD1 (an ER-associated E3 ubiquitin ligase) ubiquitinates ACSL3 and promotes its proteasomal degradation; HRD1 knockdown increases ACSL3 levels, suppresses fatty acid synthesis, promotes fatty acid oxidation, and alleviates alcohol-induced hepatic injury and steatosis. AAV9-shRNA knockdown of HRD1 and ACSL3 in mice, siRNA in HepG2 cells, co-immunoprecipitation for HRD1-ACSL3 interaction, ubiquitination assay, lipid metabolism measurements, Lieber-DeCarli ethanol diet model Toxicology letters High 41130543
2025 SUMO2 directly binds ACSL3 and inhibits its entry into the ubiquitin-proteasome degradation pathway, stabilizing ACSL3 protein and thereby suppressing ferroptosis in hepatocellular carcinoma cells; ACSL3 knockdown in SUMO2-overexpressing cells reverses SUMO2's anti-ferroptotic effect. Co-immunoprecipitation for SUMO2-ACSL3 interaction, ACSL3 ubiquitination assay, SUMO2 overexpression/knockdown, ACSL3 rescue knockdown, ferroptosis marker assays Discover oncology Medium 40526170
2025 ACSL3 knockdown impairs starvation-induced autophagy and causes formation of enlarged autophagosome-like structures negative for WIPI2; ACSL3 overexpression induces WIPI2-positive but LC3-negative dots under normal nutrition; both effects are independent of ACSL3 enzymatic activity, suggesting ACSL3 functions in formation of fusion-competent autophagosomal membranes at a stage distinct from ACSL4. Knockdown and overexpression of ACSL3 and ACSL4, autophagy induction by starvation, immunofluorescence for WIPI2, LC3, FIP200, LC3 lipidation assay, enzymatic activity-dead mutants Journal of cell science High 40728409
2025 ACSL3 is required for lipid droplet biogenesis during starvation and for formation of functional autophagosomes; under starvation ACSL3 is regulated by SYNTAXIN17; ACSL3 functions at an early autophagy stage (formation of autophagosomes) independently of its enzymatic activity. Knockdown of ACSL3, immunofluorescence for autophagy markers (FIP200, WIPI2, LC3), lipid droplet staining, genetic epistasis with SYNTAXIN17 Autophagy reports Medium 41346954
2025 Vitamin A and ATRA directly target ACSL3 and enhance its enzymatic activity; this ACSL3-dependent mechanism increases the MUFA/PUFA ratio in phospholipids, preventing lipid peroxidation and suppressing ferroptosis; vitamin A and its analogue D3 extend C. elegans lifespan in an ACSL3-dependent manner. Biochemical binding and enzymatic activity assays, phospholipid lipidomics (MUFA/PUFA ratio), ferroptosis assays, VA analogue structure-activity relationship, C. elegans lifespan assay with ACSL3 genetic dependence Acta pharmaceutica Sinica. B High 41909752
2025 ACSL3 promotes synthesis of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), which activates the PPARα pathway and enhances transcription of downstream lipid metabolism genes, promoting hepatocellular carcinoma growth and metastasis by accelerating lipid catabolism and anabolism. Proteomic and scRNA-seq analysis, ACSL3 siRNA/nanoparticle-mediated knockdown, lipidomics (POPC measurement), PPARα pathway reporter assays, in vitro and in vivo tumor models Molecular cancer Medium 40059153
2025 HNRNPC binds to ACSL3 RNA and promotes exon 10 skipping (alternative splicing), generating a short ACSL3-S isoform; m6A modification at the ACSL3 mRNA enhances HNRNPC binding; FBXW11 acts as an E3 ubiquitin ligase to ubiquitinate and degrade HNRNPC; HNRNPC knockdown in mice alleviates preeclampsia symptoms and dysregulates ferroptosis markers. RT-PCR and RT-qPCR for splicing analysis, co-IP for HNRNPC-ACSL3 RNA binding, m6A site mutation, in vitro ubiquitination assay, FBXW11 co-IP, mouse preeclampsia model with HNRNPC knockdown Journal of hypertension Medium 41037014
2025 METTL7B promotes m6A modification on ACSL3 mRNA, stabilizing its expression and inhibiting erastin-induced ferroptosis in bladder cancer cells; METTL7B knockdown reduces ACSL3 protein levels and induces ferroptosis; ACSL3 overexpression rescues the pro-ferroptotic effect of METTL7B knockdown. MeRIP for m6A modification, METTL7B knockdown/overexpression, ACSL3 expression analysis, ferroptosis assays (lipid ROS, Fe2+, MDA), ACSL3 rescue experiment, xenograft mouse model Biology direct Medium 39833962
2025 NT5DC2 interacts with ACSL3 and inhibits its ubiquitination, thereby stabilizing ACSL3 protein and suppressing ferroptosis in bladder cancer cells; silencing NT5DC2 abrogates oleic acid-mediated ACSL3 upregulation and increases ferroptosis. Co-immunoprecipitation for NT5DC2-ACSL3 interaction, ubiquitination assay, NT5DC2 knockdown, ACSL3 rescue experiment, ferroptosis assays, oleic acid treatment Cell death discovery Medium 41974665
2025 PPARγ transcriptionally upregulates ACSL3 expression (confirmed by dual-luciferase reporter assay); the AngII-AT1R axis inhibits the PPARγ/ACSL3 pathway in hippocampal neurons, promoting ferroptosis and cognitive impairment under hypertensive conditions; ACSL3 overexpression alleviates AngII-induced neuronal ferroptosis. Dual-luciferase reporter assay for PPARγ binding to ACSL3 promoter, PPARγ agonist (rosiglitazone) treatment, ACSL3 overexpression, ferroptosis markers, behavioral tests in hypertensive rat model Experimental neurology Medium 41933714
2026 Genome-wide CRISPR loss-of-function screen identifies ACSL3 as a central determinant of hepatocyte susceptibility to palmitate-induced lipotoxicity; genetic deletion or pharmacological inhibition of ACSL3 renders hepatocytes resistant to palmitate-induced apoptosis and ER stress, reduces lipid droplet accumulation, and decreases saturated fatty acid incorporation into neutral lipids and phospholipids, blunting lipogenic programs. Genome-wide CRISPR-Cas9 screen, genetic ACSL3 deletion and pharmacological inhibition, isotope tracing for fatty acid incorporation into lipid classes, lipid droplet quantification, apoptosis/ER stress assays, human MASLD tissue analysis, single-cell and spatial transcriptomics Hepatology communications High 41564380
2024 Sec14L6 directly interacts with ACSL3, and this interaction facilitates Sec14L6 targeting to lipid droplets and activates its PS transfer activity in vitro, linking ACSL3 to phospholipid transport for lipid droplet biogenesis. Co-immunoprecipitation for Sec14L6-ACSL3 interaction, in vitro PS transfer activity assay, Sec14L6 KO and rescue with lipid transfer-defective mutants, lipid droplet quantification bioRxivpreprint Medium bio_10.1101_2024.10.20.619318

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Relation of DNA methylation of 5'-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PloS one 283 19221603
2022 Baicalein ameliorates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via regulating GPX4/ACSL4/ACSL3 axis. Chemico-biological interactions 175 36055377
2022 ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers. Cancers 155 36497375
2022 ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma. Cancer & metabolism 104 36192773
2018 Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis. Cell metabolism 87 29514066
2022 Activation of MAT2A-ACSL3 pathway protects cells from ferroptosis in gastric cancer. Free radical biology & medicine 66 35182729
2017 ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells. Cancer science 63 28771887
2013 Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid. PloS one 62 23840832
2020 ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression. Science advances 55 33127675
2020 Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases. Bioscience reports 53 32286604
2018 The endogenous subcellular localisations of the long chain fatty acid-activating enzymes ACSL3 and ACSL4 in sarcoma and breast cancer cells. Molecular and cellular biochemistry 53 29450800
2007 Transcriptional activation of hepatic ACSL3 and ACSL5 by oncostatin m reduces hypertriglyceridemia through enhanced beta-oxidation. Arteriosclerosis, thrombosis, and vascular biology 53 17761945
2011 ACSL3 and GSK-3β are essential for lipid upregulation induced by endoplasmic reticulum stress in liver cells. Journal of cellular biochemistry 52 21328461
2017 Characterization of Acyl-CoA synthetase isoforms in pancreatic beta cells: Gene silencing shows participation of ACSL3 and ACSL4 in insulin secretion. Archives of biochemistry and biophysics 44 28193492
2021 Rab18 binds PLIN2 and ACSL3 to mediate lipid droplet dynamics. Biochimica et biophysica acta. Molecular and cell biology of lipids 43 33713834
2010 Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells. Journal of lipid research 41 20219900
2020 The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer. Oncogene 40 32034305
2010 The Lyn kinase C-lobe mediates Golgi export of Lyn through conformation-dependent ACSL3 association. Journal of cell science 40 20605918
2023 FTO Sensitizes Oral Squamous Cell Carcinoma to Ferroptosis via Suppressing ACSL3 and GPX4. International journal of molecular sciences 35 38003537
2025 Monounsaturated fatty acids promote cancer radioresistance by inhibiting ferroptosis through ACSL3. Cell death & disease 26 40102409
2024 METTL3 in cancer-associated fibroblasts-derived exosomes promotes the proliferation and metastasis and suppresses ferroptosis in colorectal cancer by eliciting ACSL3 m6A modification. Biology direct 25 39160584
2020 ACSL3 is a novel GABARAPL2 interactor that links ufmylation and lipid droplet biogenesis. Journal of cell science 24 32843575
2025 Modulating lipid metabolism by nanoparticles (NPs)-mediated ACSL3 silencing to inhibit hepatocellular carcinoma growth and metastasis. Molecular cancer 23 40059153
2024 ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis. Cancer biology & medicine 18 38953696
2023 miR-202-5p Inhibits Lipid Metabolism and Steroidogenesis of Goose Hierarchical Granulosa Cells by Targeting ACSL3. Animals : an open access journal from MDPI 16 36766213
2023 The BRD4-SRPK2-SRSF2 signal modulates the splicing efficiency of ACSL3 pre-mRNA and influences erastin-induced ferroptosis in osteosarcoma cells. Cell death & disease 15 37993451
2024 ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3. Clinical and translational medicine 13 39285846
2020 Genotypes and haplotype combination of ACSL3 gene sequence variants is associated with growth traits in Dezhou donkey. Gene 13 32217139
2025 Methyltransferase-like 7B participates in bladder cancer via ACSL3 m6A modification in a ferroptosis manner. Biology direct 10 39833962
2024 IL15RA-STAT3-GPX4/ACSL3 signaling leads to ferroptosis resistance in pancreatic cancer. Acta biochimica et biophysica Sinica 10 39396119
2024 Transcription factor MEF2D regulates aberrant expression of ACSL3 and enhances sorafenib resistance by inhibiting ferroptosis in HCC. Frontiers in pharmacology 9 39744125
2014 Molecular cloning of the goose ACSL3 and ACSL5 coding domain sequences and their expression characteristics during goose fatty liver development. Molecular biology reports 9 24469710
2024 G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells. Nature communications 7 38879607
2024 ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer's disease. GeroScience 6 39532829
2024 TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3. Free radical biology & medicine 6 39743027
2023 MnO2 nanoparticles and MnSO4 differentially affected hepatic lipid metabolism through miR-92a/acsl3-dependent de novo lipogenesis in yellow catfish Pelteobagrusfulvidraco. Environmental pollution (Barking, Essex : 1987) 6 37598932
2025 BPDE induces ferroptosis in hippocampal neurons through ACSL3 suppression. Neurotoxicology 5 39826883
2025 Lipid Metabolism Related Gene ACSL3 as a Biomarker for Predicting Immunotherapy Outcomes in Lung Adenocarcinoma. Cancer research and treatment 5 39842163
2024 Circ_0124346 facilitates cell proliferation of pancreatic adenocarcinoma cells by regulating lipid metabolism via miR-223-3p/ACSL3 axis. Discover oncology 4 39556281
2025 UCP2 Upregulates ACSL3 to Enhance Lipid Droplet Release from Acinar Cells and Modulates the Sirt1/Smad3 Pathway to Promote Macrophage-to-Myofibroblast Transition in Chronic Pancreatitis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40874461
2025 SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma. Discover oncology 2 40526170
2025 Different roles of ACSL3 and ACSL4 in autophagosome formation. Journal of cell science 2 40728409
2025 ACSL3/GABARAPL2 Ameliorates Vascular Endothelial Cell Aging and Injury Through Protective Autophagy to Alleviate Ferroptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 40802494
2026 ACSL3 Promotes Hepatocellular Carcinoma Tumorigenesis and Correlates With JAK-STAT3 Signaling. Cancer medicine 1 41667906
2025 Multidimensional analysis reveals the potential of ACSL3 as a cancer biomarker: from pan-cancer exploration to functional validation in hepatocellular carcinoma. Clinical and experimental medicine 1 41171313
2025 Vitamin A and its analogues modulate MUFAs metabolism to improve ferroptosis and aging by direct targeting of ACSL3. Acta pharmaceutica Sinica. B 1 41909752
2023 [Research advances on the role of ACSL3 in the atherosclerosis]. Sheng li xue bao : [Acta physiologica Sinica] 1 37583046
2026 Genome-wide CRISPR screen identifies ACSL3 as a regulator of lipotoxicity and progression of MASLD. Hepatology communications 0 41564380
2026 AngII promotes hippocampal neuron ferroptosis via inhibiting the PPARγ/ACSL3 axis leading to hypertension-related cognitive impairment. Experimental neurology 0 41933714
2026 NT5DC2 inhibits ferroptosis by stabilizing ACSL3 in bladder cancer. Cell death discovery 0 41974665
2026 Vitamin D Mitigates Klebsiella pneumoniae-Induced Pneumonia by Regulating Macrophage Polarization Through miR-223/ACSL3 Axis-Mediated Lipid Metabolism Reprogramming. The journal of gene medicine 0 42002520
2025 HNRNPC aggravates the symptoms of preeclampsia by regulating m6A-dependent alternative splicing of ACSL3. Journal of hypertension 0 41037014
2025 HRD1 promotes chronic alcoholic liver disease by mediating ACSL3 ubiquitination and degradation. Toxicology letters 0 41130543
2025 Oleic Acid Improves Goat Sperm Quality by Enhancing the MBOAT2/ACSL3 Pathway to Attenuate Ferroptosis. Animals : an open access journal from MDPI 0 41301966
2025 Involvement of ACSL3 in the formation of autophagosomes and lipid droplets during starvation conditions. Autophagy reports 0 41346954
2024 Core promoter identification and transcriptional regulation of porcine ACSL3 gene. Animal biotechnology 0 39584470

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