Acyl-CoA synthetase long chain family member 4

Overview

Acyl-CoA synthetase long chain family member 4 (ACSL4) is a long-chain acyl-CoA synthetase that has emerged as an important regulator of lipid metabolism and ferroptosis. In biomedical research, ACSL4 is commonly discussed as a pro-ferroptotic factor because it contributes to the remodeling of membrane phospholipids with polyunsaturated fatty acids, thereby increasing susceptibility to lipid peroxidation. As a result, ACSL4 is frequently studied in cancer biology, metabolic disease, and ischemia-reperfusion injury, where altered ferroptotic signaling can influence cell survival, tissue damage, and treatment response.

Recent studies have placed ACSL4 within broader redox and lipid-metabolic networks involving GPX4, SLC7A11, Nrf2, HO-1, TFR1, and related inflammatory mediators. In these contexts, ACSL4 is not typically treated as a standalone biomarker, but as part of a mechanistic axis that links iron handling, glutathione depletion, oxidative stress, and membrane lipid damage. This makes ACSL4 a recurring target in experimental work on ferroptosis modulation across liver disease, reproductive toxicity, cerebral ischemia, and multiple cancer models.

Focus of Latest Publications

Recent publications have continued to implicate Acyl-CoA synthetase long chain family member 4 (ACSL4) as a key regulator of ferroptosis across diverse disease models, particularly in cancer and ischemic injury. In pancreatic cancer, Schisandrin B was reported to inhibit proliferation and induce cell death in vitro and suppress tumor growth in vivo, with transcriptomic and mechanistic analyses indicating enrichment of ferroptosis-related pathways. The study found that Schisandrin B promoted iron overload, lipid peroxidation, and glutathione depletion, altered ferroptosis-associated proteins including ACSL4, and directly interacted with ACSL4 by DARTS and molecular docking. Silencing ACSL4 partially reversed the anti-proliferative and ferroptotic effects, supporting an ACSL4-dependent mechanism.

ACSL4 was also linked to inflammatory and environmental stress responses in asthma. In PM2.5-exposed M2 macrophages, activation of the Fra2/LCN2 axis was shown to trigger ferroptosis, with coordinated downregulation of FTH1 and upregulation of ACSL4 and PTGS2. The study used integrated multi-omics profiling, ChIP-qPCR, transmission electron microscopy, and functional assays, and found that macrophage-specific LCN2 knockdown reversed PM2.5-induced mitophagy inhibition and ferroptosis, improving airway inflammation and lung function in asthmatic mice. These findings place ACSL4 within a Fra2/LCN2-driven ferroptotic program in macrophages.

In cerebral ischemia/reperfusion injury, salvianolic acid B was investigated for its protective effects after middle cerebral artery occlusion. The study reported that salvianolic acid B reduced infarct volume and improved neurological outcomes while suppressing pro-ferroptotic mediators ACSL4 and TFR1 and enhancing Nrf2 nuclear translocation with downstream HO-1 and GPX4 upregulation. The authors concluded that downregulation of ACSL4, together with activation of the Nrf2/HO-1 antioxidant pathway, cooperatively inhibited ferroptosis and preserved microvascular integrity.

ACSL4 has also emerged as a therapeutic vulnerability in drug resistance. In neurofibroma, a pH-responsive silver nanoparticle platform delivering Triacsin C, an inhibitor of long-chain acyl-CoA synthetases, was shown to reduce tumor growth, migration, and invasion while promoting apoptosis. Multi-omics analyses linked the antitumor effect to ACSL4 downregulation, remodeling of arachidonic-acid-enriched phospholipids, and increased lipid peroxidation, suggesting enhanced ferroptosis susceptibility and resensitization to MEK inhibitors. In castration-resistant prostate cancer, diminished decorin expression was associated with enzalutamide resistance and ferroptosis suppression; decorin overexpression activated PKCβII, enhanced phosphorylation of ACSL4, promoted lipid remodeling, and restored ferroptosis-dependent sensitivity to enzalutamide.

Key Publications

NEWJun Schisandrin B exhibits anti‑proliferative effects by inducing ferroptosis in pancreatic cancer. (Oncology reports, 2026, PMID 42318966): "In conclusion, Sch B may exert anti‑proliferative effects at least partially by inducing ACSL4‑dependent ferroptosis in PC."
May Targeting the Fra2/LCN2 axis attenuates PM2.5-aggravated asthma by suppressing M2 macrophage ferroptosis. (Redox biology, 2026, PMID 42214888): "The Fra2/LCN2 axis activation triggers ferroptosis via coordinated downregulation of FTH1 and upregulation of ACSL4 and PTGS2."
Jun Nuclear Factor Erythroid 2-Related Factor 2-Dependent Ferroptosis Suppression by Salvianolic Acid B Preserves Microvascular Integrity and Reduces Risk Factors for Hemorrhagic Transformation After Cerebral Infarction. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42186809): "At the mechanistic level, Sal B suppressed pro-ferroptotic mediators ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating its downstream effectors HO-1 and GPX4."
May A pH-responsive silver nanoparticle platform overcomes MEK inhibitor resistance in neurofibroma via triacsin C-mediated lipid metabolic reprogramming. (Apoptosis : an international journal on programmed cell death, 2026, PMID 42177691): "Multi-omics analyses indicated that its antitumor activity was associated with ACSL4 downregulation, remodeling of arachidonic-acid-enriched phospholipids, enhanced lipid peroxidation, and increased lipid-droplet accumulation, suggesting heightened ferroptosis susceptibility."
Jun Synergistic induction of ferroptosis by paclitaxel and sunitinib is mediated through SLC7A11 in lung cancer. (International immunopharmacology, 2026, PMID 41955701): "Mechanistically, the combination concurrently downregulates ferroptosis suppressors (FTH1, GPX4, SLC7A11) and upregulates the pro-ferroptotic enzyme ACSL4, leading to iron accumulation, glutathione depletion, and lethal lipid peroxidation."
May Diminished expression of decorin drives enzalutamide resistance in CRPC by suppressing ACSL4-dependent lipid remodeling and ferroptosis. (International immunopharmacology, 2026, PMID 41861540): "Mechanistically, DCN activated calcium-dependent Protein Kinase C Beta II (PKCβII), thereby enhancing phosphorylation of long-chain acyl-CoA synthetase 4 (ACSL4) to regulate lipid remodeling and promote ferroptosis."