Affinage

ACSL4

Long-chain-fatty-acid--CoA ligase 4 · UniProt O60488

Length
711 aa
Mass
79.2 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACSL4 (FACL4) is a long-chain acyl-CoA synthetase that activates polyunsaturated fatty acids—with marked preference for arachidonic acid—and esterifies them into membrane phospholipids, thereby supplying the peroxidation substrates that license ferroptotic cell death (PMID:9598324, PMID:27842070). Loss-of-function point mutations and genomic deletions that abolish its enzymatic activity cause nonspecific X-linked mental retardation and the Alport-syndrome-with-mental-retardation contiguous gene deletion phenotype (PMID:9480748, PMID:11889465, PMID:12525535). In ferroptosis, ACSL4 acts downstream of or parallel to GPX4: combined Gpx4/Acsl4 ablation confers resistance, and ACSL4 enriches membranes with long ω6 PUFAs that become peroxidation substrates (PMID:27842070), with its partner enzymes MMD/MBOAT7 channeling arachidonate into specific phospholipid species (PMID:37691145). Its pro-ferroptotic output is set by a dense post-translational and transcriptional control network: PKCβII phosphorylation activates ACSL4 in a lipid-peroxidation feedback loop (PMID:35027735), whereas CDK1 phosphorylation, CARM1 methylation, and several E3 ligases (UBR5, RNF25, FBXO10, TRIM21, Parkin) drive its ubiquitin-dependent degradation, opposed by stabilizing SUMOylation (TRIM28), acetylation (HAT1 at K383), and deubiquitination (USP15) (PMID:37428466, PMID:37946697, PMID:37059712, PMID:39875520, PMID:40050614, PMID:38182686, PMID:40370554). Transcription is driven by Sp1, STAT1/IRF1, STAT3, E2F downstream of RB1 loss, and a YAP/EGR1 axis, and repressed by HIF-1α, while m6A writers/erasers (METTL3/YTHDC1, FTO) tune ACSL4 mRNA stability (PMID:30737476, PMID:37611494, PMID:36928314, PMID:39889877, PMID:33444733, PMID:38852200, PMID:38834654). Beyond ferroptosis, ACSL4-driven phospholipid remodeling enhances membrane fluidity and lipid-raft–dependent integrin β1/FAK signaling to promote metastatic extravasation, and reprograms lipid metabolism through c-Myc/SREBP1 lipogenesis and FAO-fueled histone acetylation (PMID:39591965, PMID:38471082, PMID:33340617, PMID:39700137). ACSL4 mitochondrial translocation is a regulated step that sensitizes cells to mitochondria-associated ferroptosis (PMID:36367849, PMID:38218357, PMID:37627584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Establishing that ACSL4 is an enzyme—a long-chain acyl-CoA synthetase preferring arachidonic acid—defined its core biochemical activity and tissue distribution before any disease or ferroptosis role was known.

    Evidence cDNA cloning, enzymatic activity assays, Northern blot, and FISH localization to Xq23

    PMID:9480748 PMID:9598324

    Open questions at the time
    • Structural basis of arachidonate selectivity not resolved
    • Subcellular distribution of activity not defined
  2. 2002 High

    Patient missense/splice mutations that reduce enzymatic activity causally linked ACSL4 loss-of-function to X-linked mental retardation, proving the enzyme's physiological importance in brain.

    Evidence Mutation identification with enzymatic activity measurement in patient lymphoblastoid lines and co-segregation/X-inactivation analysis

    PMID:11889465 PMID:12525535

    Open questions at the time
    • Neuronal substrate/pathway downstream of ACSL4 in cognition not defined
    • Mechanism connecting reduced acyl-CoA synthesis to MR unknown
  3. 2016 High

    Unbiased genetic screens placed ACSL4 as an essential, substrate-supplying enzyme for ferroptosis, reframing it from a generic lipid enzyme to a determinant of a regulated cell death pathway.

    Evidence Genome-wide CRISPR screen, Gpx4/Acsl4 double-knockout genetics, lipidomics, plus shRNA/overexpression with 5-HETE pharmacology

    PMID:27565726 PMID:27842070

    Open questions at the time
    • Whether ACSL4 acts upstream, parallel, or downstream of GPX4 not fully resolved
    • Identity of the critical peroxidized phospholipid species not pinned down in 2016
  4. 2022 High

    Discovery of PKCβII activating phosphorylation and CDK1/UBR5-mediated degradative phosphorylation showed ACSL4 ferroptotic output is gated by opposing post-translational switches.

    Evidence CRISPR and kinase-inhibitor screens, phosphosite mutagenesis (S447), ubiquitination site mapping (K388/K498/K690), lipidomics, and xenografts

    PMID:35027735 PMID:37428466

    Open questions at the time
    • Stoichiometry and interplay between activating and degradative phosphorylation unresolved
    • Phosphatases reversing these marks not identified
  5. 2022 High

    Immune and ischemic contexts defined transcriptional and substrate-channeling control of ACSL4: IFNγ/T-cell-driven arachidonate incorporation enables immunogenic ferroptosis, while Sp1 and HIF-1α set opposing transcriptional tone.

    Evidence Lipidomics with genetic ACSL4 deletion in tumors, IFNγ + fatty-acid assays, promoter-binding/siRNA and HIF-1α manipulation in ischemia models

    PMID:30737476 PMID:33444733 PMID:35216678

    Open questions at the time
    • Direct transcription-factor occupancy at promoter not biochemically resolved for all factors
    • How substrate availability and transcription are coordinated in vivo unclear
  6. 2023 High

    A broad regulatory network was mapped: direct partners (STING, FUNDC1, MMD/MBOAT7), additional transcriptional inputs (RB1/E2F, STAT1/IRF1, FOXO3a, c-Myc/SREBP1), and a methylation-coupled degradation axis (CARM1/RNF25, FBXO10) that together tune ACSL4 level and ferroptosis or lipogenesis output.

    Evidence Co-IP/LC-MS interaction mapping, methylation/ubiquitination site assays, lipidomics, promoter analyses, and in vivo disease models across kidney, brain, and cancer

    PMID:33340617 PMID:36923928 PMID:36928314 PMID:37059712 PMID:37533255 PMID:37611494 PMID:37691145 PMID:37946697 PMID:39326685

    Open questions at the time
    • Whether these partner interactions are direct vs. complex-mediated not uniformly established
    • Tissue-specific dominance among competing regulators unclear
  7. 2024 High

    ACSL4 was shown to drive cancer metastasis independent of cell death—remodeling membrane phospholipids to raise fluidity and activate lipid-raft integrin β1/FAK signaling, and rerouting metabolism into lipogenesis and FAO-fueled histone acetylation.

    Evidence In vivo CRISPR metastasis screens, membrane-fluidity and lipid-raft fractionation assays, CD47/integrin β1/FAK readouts, and acetyl-CoA/histone-acetylation profiling

    PMID:38471082 PMID:39591965 PMID:39700137

    Open questions at the time
    • How a single enzyme partitions between pro-death and pro-metastatic phospholipid pools is unresolved
    • Direct phospholipid species responsible for raft/integrin activation not fully defined
  8. 2024 Medium

    RNA-level (m6A via METTL3/YTHDC1 and FTO) and metabolite-level (lactylation, acetylation) control further refined how ACSL4 abundance and activity respond to the metabolic environment.

    Evidence m6A modification and mRNA-stability assays, lactylation site mapping (K412), acetylation site mapping (K383) with writer/eraser manipulation in disease models

    PMID:38834654 PMID:38852200 PMID:40050614 PMID:40171826

    Open questions at the time
    • Cross-talk hierarchy among mRNA, lactylation, and acetylation controls not integrated
    • Direct catalytic consequence of each PTM on enzyme kinetics not measured
  9. 2025 High

    Cell-type-resolved genetics revealed ACSL4 acts non-cell-autonomously, with fibroblast ACSL4 dictating ferroptosis sensitivity of neighboring epithelium, expanding its role to heterocellular tissue crosstalk in inflammation.

    Evidence Fibroblast-specific gain- and loss-of-function in multiple colitis models with lipid metabolism and ferroptosis readouts

    PMID:40571769

    Open questions at the time
    • Identity of the transferred lipid mediator between fibroblasts and epithelium unknown
    • Generalizability beyond intestinal tissue untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ACSL4 substrate flux is partitioned between pro-ferroptotic phospholipids, neutral lipids/triglycerides, and pro-metastatic raft lipids, and what structural features dictate this context-dependent channeling.
  • No structural model linking active-site chemistry to lipid product fate
  • Context-dependence (e.g., ER-stress AKI directing PUFA to triglyceride rather than phospholipid) mechanistically unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0008289 lipid binding 3 GO:0016740 transferase activity 3
Localization
GO:0005739 mitochondrion 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
FBXO10FUNDC1MBOAT7MMDRNF25STINGTRIM28UBR5

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 ACSL4 is an essential component for ferroptosis execution; Gpx4-Acsl4 double-knockout cells show marked resistance to ferroptosis, placing ACSL4 downstream of or parallel to GPX4. Mechanistically, ACSL4 enriches cellular membranes with long polyunsaturated ω6 fatty acids, providing peroxidation substrates required for ferroptosis. Genome-wide CRISPR-based genetic screen, microarray analysis of resistant cell lines, Gpx4/Acsl4 double-knockout mouse genetics, lipidomics Nature chemical biology High 27842070
2016 ACSL4-mediated production of 5-hydroxyeicosatetraenoic acid (5-HETE) contributes to ferroptosis; knockdown of ACSL4 inhibits erastin-induced ferroptosis in sensitive cells, while overexpression restores ferroptosis sensitivity in resistant cells. shRNA knockdown, gene transfection overexpression, pharmacological inhibition of 5-HETE production (zileuton), cell death assays Biochemical and biophysical research communications Medium 27565726
1998 ACSL4 (FACL4) encodes a functional long-chain fatty acid-CoA ligase with substrate preference for arachidonic acid; the gene is located on chromosome Xq23 and is highly expressed in brain, placenta, testis, ovary, spleen, and adrenal cortex. cDNA cloning, enzymatic activity assay, Northern hybridization, FISH chromosomal localization Genomics High 9598324
1998 FACL4 (ACSL4) encodes a long-chain acyl-CoA synthetase of 670 amino acids (711 in brain isoform); the gene is deleted in patients with Alport syndrome with mental retardation, establishing loss of ACSL4 enzymatic function as contributing to the MR phenotype. Genomic deletion mapping, RACE cloning, Northern blot, sequence conservation analysis Genomics Medium 9480748
2002 Point mutations in FACL4 (ACSL4) causing reduced enzymatic activity lead to nonspecific X-linked mental retardation; analysis of lymphoblastoid cell lines from affected individuals showed low levels of fatty acid-CoA ligase enzymatic activity, confirming loss-of-function. Mutation identification (missense and splice-site), enzymatic activity assay in lymphoblastoid cell lines, X-inactivation analysis Nature genetics High 11889465
2003 A missense mutation (P375L) in the first luciferase domain of FACL4 markedly reduces enzymatic activity and co-segregates with MRX68; a rapid enzymatic assay on peripheral blood is sufficient for diagnostic screening. Mutation screening, enzymatic activity assay on peripheral blood, co-segregation analysis Journal of medical genetics Medium 12525535
2022 PKCβII phosphorylates and activates ACSL4, amplifying lipid peroxidation and ferroptosis; PKCβII acts as a sensor of initial lipid peroxides and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis drives ferroptosis. Activated ACSL4 catalyzes PUFA-containing lipid biosynthesis, leading to accumulation of lipid peroxidation products. Genome-wide CRISPR-Cas9 screen, kinase inhibitor library screen, phosphorylation assays, lipidomics, in vitro and in vivo functional studies Nature cell biology High 35027735
2022 CDK1 directly binds to and phosphorylates ACSL4 at S447, triggering recruitment of E3 ubiquitin ligase UBR5 and polyubiquitination of ACSL4 at K388, K498, and K690, leading to ACSL4 protein degradation and consequent suppression of ferroptosis. CRISPR/Cas9 screening, direct binding assays, phosphorylation site mutagenesis, ubiquitination assays, mass spectrometry, xenograft models Advanced science High 37428466
2022 IFNγ stimulates ACSL4 and alters tumor cell lipid patterns, increasing incorporation of arachidonic acid into C16 and C18 acyl chain-containing phospholipids, thereby enabling CD8+ T cell-mediated immunogenic tumor ferroptosis. Palmitoleic acid and oleic acid promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus arachidonic acid. Lipidomics, genetic ACSL4 deletion in tumors, in vivo tumor models, combination IFNγ + fatty acid treatment assays Cancer cell High 35216678
2019 Sp1 is a transcription factor that increases ACSL4 transcription by binding to the ACSL4 promoter region during ischemia-induced ferroptosis in intestinal ischemia/reperfusion injury. Promoter binding assay (Sp1 binding to ACSL4 promoter), siRNA knockdown, in vivo and in vitro ischemia/hypoxia models, pharmacological inhibition with rosiglitazone Cell death and differentiation Medium 30737476
2021 HIF-1α negatively regulates ACSL4 expression; ACSL4 expression is suppressed in the early phase of ischemic stroke by HIF-1α induction, and overexpression of ACSL4 exacerbates ischemic brain injury via enhanced lipid peroxidation/ferroptosis. ACSL4 knockdown/overexpression in vivo, HIF-1α manipulation, lipid peroxidation assays, in vivo ischemia models Brain, behavior, and immunity Medium 33444733
2022 Thrombin promotes arachidonic acid mobilization and subsequent esterification by ACSL4, generating pro-ferroptotic phosphatidylethanolamine lipid products; multi-omics identified thrombin and ACSL4 as prominently altered in middle cerebral artery occlusion. Genetic or pharmacological inhibition of this pathway attenuated ischemic outcomes. Unbiased multi-omics (proteomics, lipidomics), genetic and pharmacological inhibition of thrombin-ACSL4 pathway, in vitro and in vivo ischemia models Signal transduction and targeted therapy Medium 35197442
2024 ACSL4 compound AS-252424 directly binds to glutamine 464 of ACSL4 to inhibit its enzymatic activity, suppressing lipid peroxidation and ferroptosis; identified via kinase inhibitor library screening and validated with binding and enzymatic assays. Kinase inhibitor library screening, direct binding assay, enzymatic activity assay with site-specific mutation (Q464), nanoparticle delivery in vivo Science advances High 38552012
2021 ACSL4-mediated lipid peroxidation/ferroptosis pathway is regulated by the transcription factor SP1, which promotes ACSL4 expression; inhibition of SP1 or ACSL4 rescues Aβ-induced cardiomyocyte lipid peroxidation defects in the context of ALDH2-mediated protection. SP1 inhibitor (tolfenamic acid), ACSL4 inhibitor (triacsin C), cardiomyocyte in vitro models, ALDH2 transgenic mice Acta pharmacologica Sinica Medium 33767380
2022 GLIA maturation factor-β (GMFB) impairs chaperone-mediated autophagy (CMA) degradation of ACSL4: GMFB translocates ATP6V1A from lysosomes preventing assembly and alkalinizing lysosomes, blocking HSC70-mediated autophagic digestion of ACSL4, leading to ACSL4 accumulation and ferroptosis in retinal pigment epithelial cells. Protein interaction/co-localization, lysosomal pH assays, CMA pathway perturbation, HSC70 recognition assay, in vitro and in vivo diabetic retinopathy models Redox biology Medium 35325805
2023 CARM1 methylates ACSL4 at arginine 339 (R339); this methylation promotes binding of E3 ubiquitin ligase RNF25 to ACSL4, leading to ACSL4 ubiquitylation and degradation. Inhibition of CARM1 thus stabilizes ACSL4 and increases ferroptosis sensitivity. Methylation site identification (R339), RNF25 co-IP and binding assays, ubiquitination assays, in vitro and in vivo ferroptosis assays Advanced science High 37946697
2023 CYP1B1-derived 20-HETE activates the protein kinase C pathway to increase FBXO10 expression, which promotes ubiquitination and degradation of ACSL4, rendering tumor cells resistant to ferroptosis. CYP1B1 manipulation, 20-HETE treatment, FBXO10 expression analysis, ubiquitination assay for ACSL4, ferroptosis assays Cell death & disease Medium 37059712
2023 STING directly interacts with ACSL4 at D53 and K412 amino acids of ACSL4 (identified by co-immunoprecipitation and LC-MS/MS); STING induces renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Co-immunoprecipitation, liquid chromatography-tandem mass spectrometry (protein interaction mapping), ACSL4 siRNA, pharmacological inhibition, in vivo kidney injury models Molecular therapy Medium 37533255
2023 ACSL4 regulates lipid metabolism and reduces VGLL4 expression to promote NF-κB signal transduction, driving LPS-induced proinflammatory responses in microglia; knockdown of ACSL4 decreases proinflammatory cytokine production. ACSL4 knockdown in microglia, NF-κB pathway analysis, VGLL4 expression assays, LPS-induced neuroinflammation models in vitro and in vivo Brain, behavior, and immunity Medium 36791893
2023 RB1 loss activates E2F transcription factors which directly upregulate ACSL4 expression (ACSL4 is a direct E2F target gene), enriching arachidonic acid-containing phospholipids and sensitizing cells to ferroptosis via an RB/E2F/ACSL4 molecular axis. RB1 loss/E2F activation genetic models, ACSL4 promoter analysis (E2F target), lipidomics, xenograft tumor models, GPX4 inhibitor treatment in vivo The Journal of clinical investigation High 36928314
2023 TRIM28 binds to ACSL4 and promotes SUMO3 modification of ACSL4 at lysine 532, inhibiting K63-linked ACSL4 ubiquitination and thereby suppressing OPTN-dependent autophagic degradation of ACSL4, leading to ACSL4 accumulation and neuronal ferroptosis. SENP3 was identified as the deSUMOylation enzyme that reverses this process. Co-IP (TRIM28-ACSL4 binding), SUMOylation site mapping (K532), ubiquitination assays, autophagy-receptor (OPTN) analysis, Trim28 genetic deletion in mice, SCI model Cell death and differentiation High 39875520
2023 AIM2 promotes FOXO3a phosphorylation and proteasome degradation, reducing FOXO3a transcriptional activation of ACSL4 and inhibiting ferroptosis in renal cell carcinoma; this pathway drives sunitinib resistance. AIM2 overexpression/knockdown, FOXO3a phosphorylation and degradation assays, ACSL4 transcriptional regulation assays, ferroptosis assays International journal of biological sciences Medium 36923928
2023 Radiation-induced ACSL4 transcription is regulated by the STAT1/IRF1 axis; STAT1 and IRF1 drive ACSL4 upregulation in irradiated intestinal epithelial cells, promoting ferroptosis-mediated radiation intestinal injury. RNA sequencing, ACSL4 promoter/transcription analysis (STAT1/IRF1), ACSL4 knockdown, AMPK activation assays, in vivo radiation injury model Redox biology Medium 37611494
2024 Lactate induces ACSL4 expression via histone H3K18 lactylation at the ACSL4 promoter, and also directly lactylates ACSL4 at K412 (post-translational lactylation); decreased SIRT3 expression elevates ACSL4 lactylation, driving ferroptosis in nucleus pulposus cells during intervertebral disc degeneration. Single-cell RNA sequencing, H3K18 lactylation assay at ACSL4 promoter, ACSL4 K412 lactylation site identification, SIRT3 expression analysis, AAV9-siLdha in vivo, 2-DG treatment Advanced science Medium 40171826
2024 METTL3-mediated m6A modification is enriched in ACSL4 mRNA and its stability is regulated through a YTHDC1-dependent pathway; lactate promotes p300-mediated H3K18la binding to the METTL3 promoter, upregulating METTL3 which then stabilizes ACSL4 mRNA, promoting ferroptosis in alveolar epithelial cells. m6A modification assays, METTL3 knockdown/inhibition, YTHDC1 pathway analysis, H3K18la ChIP, GPR81 signaling assays, in vitro and in vivo sepsis models Redox biology Medium 38852200
2024 FTO demethylase activity targets ACSL4 and TFRC mRNA stability in an m6A-dependent manner; FTO downregulation in older livers increases ACSL4 and TFRC expression, exacerbating ferroptosis during ischemia/reperfusion injury. Mass spectrometry (FTO identification), FTO overexpression in vivo, m6A modification assays for ACSL4 mRNA, mRNA stability assays, older vs. young liver comparison Nature communications High 38834654
2023 MMD physically interacts with both ACSL4 and MBOAT7 (two enzymes catalyzing sequential steps of arachidonic acid incorporation into phosphatidylinositol), increasing flux of AA into PI and other AA-containing phospholipid species, thereby promoting ferroptosis susceptibility. Co-IP (MMD-ACSL4 and MMD-MBOAT7 interactions), lipidomics, genetic loss-of-function in ovarian and renal carcinoma cells Cell reports High 37691145
2024 ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness through PUFA-lipid incorporation; ACSL4 is a pro-hematogenous metastasis factor identified by metabolism-focused in vivo CRISPR screens in ovarian cancer. Two rounds of in vivo CRISPR screen in mouse ovarian cancer metastasis model, membrane fluidity assays, invasion assays, ACSL4 genetic deletion Cell High 39591965
2024 ACSL4-mediated phospholipid remodeling of cell membranes induces lipid-raft localization and activation of integrin β1 in a CD47-dependent manner, leading to downstream focal adhesion kinase phosphorylation that promotes TNBC metastasis. Lipidomics of metastatic vs. primary TNBC, lipid raft fractionation, integrin β1 activation assays, CD47 dependence assays, FAK phosphorylation assays, in vivo pharmacological ACSL4 inhibition Cancer research High 38471082
2024 ACSL4-mediated lipid peroxidation promotes lipid raft formation in melanoma cell membranes, which inhibits immunogenic ferroptosis and pyroptosis by reducing cell membrane pore formation; disruption of ACSL4-mediated lipid rafts (by cholesterol removal) promotes immunogenic cell death. Lipid raft isolation, ferroptosis/pyroptosis assays, cholesterol depletion experiments, ACSL4 manipulation, immune cell co-culture Cell death & disease Medium 39343834
2024 ACSL4 modulates fatty acid oxidation (FAO) and intracellular acetyl-CoA levels, leading to hyperacetylation of H3K9ac and H3K27ac marks and overexpression of SNAIL, driving TNBC metastasis via an epigenetic mechanism. Global transcriptome analysis, acetyl-CoA metabolic assays, histone acetylation (H3K9ac, H3K27ac) quantification, ACSL4 genetic ablation/pharmacological inhibition, in vivo metastasis models Proceedings of the National Academy of Sciences of the United States of America Medium 39700137
2023 ACSL4 upregulates the lipogenesis master regulator SREBP1 and its downstream lipogenic enzymes via c-Myc in HCC cells, promoting de novo lipogenesis and accumulation of triglycerides, cholesterols, and lipid droplets; SREBP1 is required for ACSL4-mediated lipogenesis and oncogenic capabilities. ACSL4 knockdown/overexpression, SREBP1 rescue experiments, c-Myc pathway analysis, lipid droplet quantification, in vitro and in vivo HCC models Cancer letters Medium 33340617
2022 ACSL4 and LPCAT2 overexpression together sensitize cells to RSL3-induced ferroptosis; mitochondrial ROS formation and mitochondrial membrane potential deterioration are essential downstream events in ACSL4/LPCAT2-driven ferroptosis, and mitoquinone (MitoQ) protection confirms mitochondrial ROS as a key mediator. ACSL4 and LPCAT2 co-overexpression in HEK293T cells, ferroptosis assays, mitochondrial ROS measurement, mitochondrial membrane potential assay, mitochondrial respiration assay, MitoQ treatment Antioxidants (Basel, Switzerland) Medium 37627584
2022 FUNDC1 (mitophagy receptor) co-immunoprecipitates with ACSL4, indicating a direct protein-protein interaction; FUNDC1 deficiency leads to upregulation of ACSL4 and enhanced ferroptosis in cardiomyocytes under high-fat diet challenge. Co-immunoprecipitation (FUNDC1-ACSL4), FUNDC1 knockout mice, ACSL4 expression analysis, ferroptosis assays, in vitro arachidonic acid treatment Free radical biology & medicine Medium 39326685
2023 HIV-1 Tat protein downregulates miR-204 in microglia, releasing its suppression of ACSL4, leading to increased ACSL4 expression, oxidized phosphatidylethanolamine generation, lipid peroxidation, and ferroptosis-driven microglial activation with proinflammatory cytokine release. miR-204 mimic transfection, ACSL4 gene silencing, lipid peroxidation assays, co-immunoprecipitation, HIV-1 transgenic rat validation, human HIV+ brain sample analysis Redox biology Medium 37023693
2025 HAT1 directly promotes acetylation of ACSL4 at lysine 383, enhancing its protein stability; SIRT3 mediates deacetylation of ACSL4, while HDAC2 enhances ACSL4 acetylation by inhibiting SIRT3 transcription. Acetylation at K383 inhibits FBXO10-mediated K48-linked ubiquitination of ACSL4, stabilizing the protein. Acetylation site mapping (K383), HAT1/SIRT3/HDAC2 manipulation, ubiquitination assays, FBXO10 interaction assay, in vitro and in vivo NPC models Cell death & disease Medium 40050614
2025 Parkin E3 ubiquitin ligase promotes ubiquitination of ACSL4, inhibiting iron overload-induced ferroptosis in cardiomyocytes; p53 transcriptionally suppresses Parkin expression in iron-overloaded cardiomyocytes, establishing a p53-Parkin-ACSL4 regulatory pathway in cardiac ferroptosis. Parkin-ACSL4 ubiquitination assays, cardiac-specific Parkin knockout mice (Myh6-CreER/Parkin), p53 transcriptional regulation of Parkin, iron overload and I/R models, ferroptosis inhibitor (Fer-1) rescue Acta pharmaceutica Sinica. B Medium 40370554
2024 TRIM21 (E3 ligase) and USP15 (deubiquitinase) together control ACSL4 protein stability: TRIM21 promotes ACSL4 degradation while USP15 stabilizes it; reduced ACSL4 expression due to excessive TRIM21-mediated degradation underlies imatinib resistance in GISTs. Co-immunoprecipitation (TRIM21-ACSL4, USP15-ACSL4), shRNA interference, Western blot, xenograft model, GIST patient sample analysis British journal of cancer Medium 38182686
2022 The silibinin (SIL) natural compound directly binds to ACSL4 at the K536-proximal region and inhibits ACSL4 enzymatic activity, mitigating ACSL4-mediated ferroptosis; living cell-target responsive accessibility profiling (LC-TRAP) identified ACSL4 as a SIL target. LC-TRAP proteomics, biophysical binding assays, SIL-derivatized chemical probe, enzymatic activity assay, site-specific binding region identification (K536-proximal) Analytical chemistry Medium 36260072
2023 MFN2 overexpression suppresses the mitochondrial translocation of ACSL4, inhibiting mitochondria-associated ferroptosis; PRDX2-mediated suppression of oxidative stress operates upstream via MFN2-dependent mitochondrial dynamics to prevent ACSL4 mitochondrial localization. MFN2 overexpression, ACSL4 mitochondrial localization by immunofluorescence, ferroptosis assays in db/db mice and cardiac microvascular endothelial cells, PRDX2 overexpression Diabetes Medium 36367849
2024 Mitochondria-localized AMPKα1 phosphorylation promotes Pink1/Parkin-dependent mitophagy, which inhibits the mitochondrial translocation of ACSL4, suppressing mitochondria-associated ferroptosis in cardiac microvascular endothelial cells during diabetic cardiomyopathy. AMPKα1 mitochondrial localization assay, mitophagy assay (mt-Keima, TEM), ACSL4 mitochondrial translocation by immunofluorescence, mitoAα1 overexpression, in vivo diabetic model Pharmacological research Medium 38218357
2023 NFIL3 (a circadian rhythm gene) directly regulates ACSL4 expression; NFIL3 knockdown attenuates ferroptosis and inflammation in renal tubular epithelial cells by downregulating ACSL4 in sepsis-associated AKI. NFIL3 loss-of-function in vitro and in vivo, ACSL4 expression analysis, ferroptosis markers, SA-AKI model Cell death discovery Low 39097582
2024 STAT3 signaling drives ACSL4 expression in tubular epithelial cells; however, in the context of ER stress-induced AKI, ACSL4 activity directs PUFA metabolism toward triglycerides rather than phospholipids, and ACSL4 alone is insufficient to sensitize cells to ferroptosis, highlighting context-dependence. STAT3 inhibition, lipidomics, ACSL4 expression analysis, mouse ER stress AKI model iScience Medium 38799564
2025 In IBD, ACSL4 is overexpressed in intestinal fibroblasts where it reprograms lipid metabolism and mediates sensitivity of adjacent intestinal epithelial cells to ferroptosis through heterocellular crosstalk; fibroblast-specific ACSL4 overexpression increases epithelial ferroptosis and worsens colitis, while fibroblast ACSL4 deletion ameliorates colitis. Fibroblast-specific ACSL4 overexpression and deletion in mouse models of colitis, IBD tissue analysis, lipid metabolism assays, ferroptosis markers Nature metabolism High 40571769
2024 EGR1 transcriptionally upregulates ACSL4 expression; YAP transcriptionally upregulates EGR1, forming a YAP/EGR1/ACSL4 axis that promotes ferroptosis in ischemic stroke; chromatin immunoprecipitation and dual luciferase assays verified these molecular interactions. Chromatin immunoprecipitation, dual luciferase assay (EGR1-ACSL4 promoter, YAP-EGR1 promoter), OGD/R neuronal models, MCAO mouse model, YAP/EGR1 overexpression/silencing Experimental neurology Medium 39889877

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature chemical biology 3318 27842070
2016 Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochemical and biophysical research communications 888 27565726
2019 Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell death and differentiation 743 30737476
2022 CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer cell 730 35216678
2022 PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nature cell biology 474 35027735
2021 ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain, behavior, and immunity 473 33444733
2022 ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury. Redox biology 365 35180475
2023 Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism. Chinese medical journal 287 37442770
2022 Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion. Signal transduction and targeted therapy 278 35197442
2023 Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 266 37003125
2024 Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. Redox biology 225 38852200
2020 ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway. Cancer letters 191 33340617
2022 Baicalein ameliorates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via regulating GPX4/ACSL4/ACSL3 axis. Chemico-biological interactions 175 36055377
2019 ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncology reports 167 31789401
2022 ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers. Cancers 155 36497375
2023 Inhibition of CDK1 Overcomes Oxaliplatin Resistance by Regulating ACSL4-mediated Ferroptosis in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 145 37428466
2019 Role of acyl-CoA synthetase ACSL4 in arachidonic acid metabolism. Prostaglandins & other lipid mediators 144 31306767
2024 ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization. Cell 140 39591965
2021 FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis. Metabolism: clinical and experimental 136 34331963
2024 Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases. Science advances 132 38552012
2022 Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy. Redox biology 132 35325805
2002 FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Nature genetics 122 11889465
2021 Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis. Acta pharmacologica Sinica 120 33767380
2023 ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries. International journal of molecular sciences 119 37373168
2023 STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease. Molecular therapy : the journal of the American Society of Gene Therapy 112 37533255
1998 Cloning, expression, and chromosomal localization of human long-chain fatty acid-CoA ligase 4 (FACL4). Genomics 110 9598324
2023 CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer. Cell death & disease 108 37059712
2023 Isorhapontigenin Attenuates Cardiac Microvascular Injury in Diabetes via the Inhibition of Mitochondria-Associated Ferroptosis Through PRDX2-MFN2-ACSL4 Pathways. Diabetes 100 36367849
2022 ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke. Journal of cachexia, sarcopenia and muscle 99 35243801
1998 FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation. Genomics 99 9480748
2023 Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis. Acta pharmacologica Sinica 98 37696989
2021 Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice. Hepatology (Baltimore, Md.) 96 34510514
2022 Hsp90 induces Acsl4-dependent glioma ferroptosis via dephosphorylating Ser637 at Drp1. Cell death & disease 94 35697672
2023 ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression. Brain, behavior, and immunity 92 36791893
2023 RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. The Journal of clinical investigation 92 36928314
1993 LE-ACS4, a fruit ripening and wound-induced 1-aminocyclopropane-1-carboxylate synthase gene of tomato (Lycopersicon esculentum). Expression in Escherichia coli, structural characterization, expression characteristics, and phylogenetic analysis. The Journal of biological chemistry 90 8366090
2023 EGCG attenuated acute myocardial infarction by inhibiting ferroptosis via miR-450b-5p/ACSL4 axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 89 37597361
2022 ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons. Free radical biology & medicine 87 36581060
2015 ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. Oncotarget 82 26636648
2022 ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics. Frontiers in pharmacology 81 35910359
2022 CRISPR/Cas9 Screens Reveal that Hexokinase 2 Enhances Cancer Stemness and Tumorigenicity by Activating the ACSL4-Fatty Acid β-Oxidation Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 75 35603967
2023 MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 72 36695612
2024 FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. Nature communications 70 38834654
2023 Ferroptosis triggered by STAT1- IRF1-ACSL4 pathway was involved in radiation-induced intestinal injury. Redox biology 68 37611494
2024 Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway. Pharmacological research 66 38218357
2022 Circular RNA circLMO1 Suppresses Cervical Cancer Growth and Metastasis by Triggering miR-4291/ACSL4-Mediated Ferroptosis. Frontiers in oncology 66 35321435
2023 Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage. Life sciences 65 37741320
2025 Glycolysis-Derived Lactate Induces ACSL4 Expression and Lactylation to Activate Ferroptosis during Intervertebral Disc Degeneration. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 61 40171826
2023 Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease. Communications biology 61 37670055
2022 ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis. Cell death discovery 58 35869042
2023 ACSL4 promotes ferroptosis and M1 macrophage polarization to regulate the tumorigenesis of nasopharyngeal carcinoma. International immunopharmacology 57 37451020
2024 ACSL4-Mediated Membrane Phospholipid Remodeling Induces Integrin β1 Activation to Facilitate Triple-Negative Breast Cancer Metastasis. Cancer research 55 38471082
2023 AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis. International journal of biological sciences 55 36923928
2023 HIV-1 Tat-mediated microglial ferroptosis involves the miR-204-ACSL4 signaling axis. Redox biology 55 37023693
2023 Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis. Antioxidants (Basel, Switzerland) 55 37627584
2023 microRNA-130b-3p Attenuates Septic Cardiomyopathy by Regulating the AMPK/mTOR Signaling Pathways and Directly Targeting ACSL4 against Ferroptosis. International journal of biological sciences 54 37705752
2023 The ACSL4 Network Regulates Cell Death and Autophagy in Diseases. Biology 51 37372148
2023 MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis. Cell reports 47 37691145
2024 Propionate promotes ferroptosis and apoptosis through mitophagy and ACSL4-mediated ferroptosis elicits anti-leukemia immunity. Free radical biology & medicine 45 38215892
2023 Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 45 37133631
2023 Inhibition of CARM1-Mediated Methylation of ACSL4 Promotes Ferroptosis in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 42 37946697
2024 A pH responsive nanocomposite for combination sonodynamic-immunotherapy with ferroptosis and calcium ion overload via SLC7A11/ACSL4/LPCAT3 pathway. Exploration (Beijing, China) 39 40040833
2023 ACSL4 inhibition prevents macrophage ferroptosis and alleviates fibrosis in bleomycin-induced systemic sclerosis model. Arthritis research & therapy 38 37884942
2003 A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients. Journal of medical genetics 36 12525535
2023 Vitamin D Attenuates Ulcerative Colitis by Inhibiting ACSL4-Mediated Ferroptosis. Nutrients 35 38004239
2022 ACSL4 is overexpressed in psoriasis and enhances inflammatory responses by activating ferroptosis. Biochemical and biophysical research communications 35 35868067
2024 The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis. Free radical biology & medicine 34 38367927
2023 RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4. Oncogene 34 38040804
2023 Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis. Cell death & disease 33 38065978
2022 ACSL4 promotes colorectal cancer and is a potential therapeutic target of emodin. Phytomedicine : international journal of phytotherapy and phytopharmacology 33 35567995
2025 Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4. Cell death and differentiation 30 39875520
2024 Curcumin promotes ferroptosis in hepatocellular carcinoma via upregulation of ACSL4. Journal of cancer research and clinical oncology 30 39311951
2022 Ferroptosis execution: Is it all about ACSL4? Cell chemical biology 30 36113403
2024 Preconditioning Exercise Inhibits Neuron Ferroptosis and Ameliorates Brain Ischemia Damage by Skeletal Muscle-Derived Exosomes via Regulating miR-484/ACSL4 Axis. Antioxidants & redox signaling 29 38545792
2024 Gastrodin: Modulating the xCT/GPX4 and ACSL4/LPCAT3 pathways to inhibit ferroptosis after ischemic stroke. Phytomedicine : international journal of phytotherapy and phytopharmacology 29 39731833
2023 YAP/ACSL4 Pathway-Mediated Ferroptosis Promotes Renal Fibrosis in the Presence of Kidney Stones. Biomedicines 29 37893066
2022 Living Cell-Target Responsive Accessibility Profiling Reveals Silibinin Targeting ACSL4 for Combating Ferroptosis. Analytical chemistry 28 36260072
2025 Scutellaria baicalensis Extracts Restrict Intestinal Epithelial Cell Ferroptosis by Regulating Lipid Peroxidation and GPX4/ACSL4 in Colitis. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 40220415
2025 Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD. Nature metabolism 27 40571769
2024 Ablation of mitophagy receptor FUNDC1 accentuates septic cardiomyopathy through ACSL4-dependent regulation of ferroptosis and mitochondrial integrity. Free radical biology & medicine 24 39326685
2023 Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury. Chemico-biological interactions 24 38056807
2024 Tongqiao Huoxue Decoction inhibits ferroptosis by facilitating ACSL4 ubiquitination degradation for neuroprotection against cerebral ischemia-reperfusion injury. Phytomedicine : international journal of phytotherapy and phytopharmacology 23 38788392
2024 Ferroptosis and inflammation are modulated by the NFIL3-ACSL4 axis in sepsis associated-acute kidney injury. Cell death discovery 23 39097582
2023 Relationship Between ACSL4-Mediated Ferroptosis and Chronic Obstructive Pulmonary Disease. International journal of chronic obstructive pulmonary disease 23 36817367
2025 ACSL4 at the helm of the lipid peroxidation ship: a deep-sea exploration towards ferroptosis. Frontiers in pharmacology 22 40932861
2014 Tomato ACS4 is necessary for timely start of and progression through the climacteric phase of fruit ripening. Frontiers in plant science 21 25278945
2024 Role of Hippo/ACSL4 axis in ferroptosis-induced pericyte loss and vascular dysfunction in sepsis. Redox biology 20 39566164
2023 Regulation of ferroptosis and ACSL4-15LO1 pathway contributed to the anti-asthma effect of acupuncture. International immunopharmacology 20 36603356
2025 HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma. Cell death & disease 18 40050614
2025 Parkin inhibits iron overload-induced cardiomyocyte ferroptosis by ubiquitinating ACSL4 and modulating PUFA-phospholipids metabolism. Acta pharmaceutica Sinica. B 18 40370554
2025 Exosomal irisin from FNDC5-engineered BMSCs improves ischemic stroke via inhibiting YAP/EGR1/ACSL4-mediated ferroptosis. Experimental neurology 17 39889877
2024 Silencing of lncRNA NEAT1 alleviates acute myocardial infarction by suppressing miR-450-5p/ACSL4-mediated ferroptosis. Experimental cell research 17 39222870
2024 ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma. Cell death & disease 17 39343834
2024 ACSL4 promotes malignant progression of Hepatocellular carcinoma by targeting PAK2 transcription. Biochemical pharmacology 16 38615921
2024 STAT3 drives the expression of ACSL4 in acute kidney injury. iScience 16 38799564
2024 ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis. Proceedings of the National Academy of Sciences of the United States of America 16 39700137
2023 ZNF8-miR-552-5p Axis Modulates ACSL4-Mediated Ferroptosis in Hepatocellular Carcinoma. DNA and cell biology 16 37126948
2024 TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors. British journal of cancer 15 38182686
2024 Salivary gland protective and antiinflammatory effects of genistein in Sjögren's syndrome by inhibiting Xist/ACSL4-mediated ferroptosis following binding to estrogen receptor-alpha. Cellular & molecular biology letters 15 39623319
2024 Paeonol inhibits ACSL4 to protect chondrocytes from ferroptosis and ameliorates osteoarthritis progression. Journal of orthopaedic translation 14 39659898

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