ACSL Family

Long-chain acyl-CoA synthetase (ACSL) serves as a central regulatory node in cellular lipid metabolism, responsible for activating free long-chain fatty acids into acyl-CoAs, thereby channeling these fatty acids into downstream pathways such as oxidative energy production or complex lipid synthesis. The mammalian ACSL family comprises five isoforms-ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6-which exhibit significant differences in their tissue distribution, subcellular localization, and substrate preferences^[1].
Specifically, ACSL3 inhibits lipid peroxidation by enriching monounsaturated fatty acids, thereby protecting tumor cells from damage. ACSL4 is predominantly enriched in adrenal and brain tissues; it specifically favors the activation of 20-carbon polyunsaturated fatty acids (PUFAs), acts as a core executor driving ferroptosis, and participates in the JAK-STAT1-IRF1 signaling axis. In various malignancies-such as hepatocellular carcinoma and breast cancer-ACSL4 exerts pro-tumorigenic effects and is associated with poor prognosis. Conversely, ACSL5 is primarily distributed in the intestine, localizes to mitochondria, and prefers 16-18 carbon fatty acids; it suppresses the Wnt signaling pathway by mediating the palmitoylation of the Wnt2B protein, typically functioning as a tumor suppressor gene and exerting protective effects in pancreatic cancer. However, in gastric cancer, ACSL5 is aberrantly overexpressed due to promoter hypomethylation, which paradoxically promotes the proliferation and metastasis of tumor cells^[1][2][3].
The expression of the ACSL family is under strict regulation by signaling pathways-such as JAK-STAT and PPAR-as well as epigenetic mechanisms; functional abnormalities within this family are closely implicated in various malignancies-including hepatocellular carcinoma and breast cancer-as well as metabolic disorders. Inhibitors specifically targeting ACSL4 and ACSL5-such as troglitazone and tolcapone-hold potential for clinical application in precisely disrupting tumor metabolism or mitigating tissue damage^[1][2][3].