ACSL3 (acyl-CoA synthetase long chain family member 3) is a long-chain fatty acid activator that catalyzes the conversion of long-chain fatty acids into acyl-CoA thioesters, facilitating their incorporation into cellular lipids and phosphatidylcholine synthesis 1. The enzyme preferentially processes myristate, laurate, arachidonate, and eicosapentaenoate 2, with localization to the endoplasmic reticulum, Golgi apparatus, and lipid droplets supporting its roles in hepatic lipogenesis and VLDL assembly 3. ACSQL3 functions as a ferroptosis suppressor by enabling oleic acid-dependent protection against iron-dependent lipid peroxidation 45. In cancer contexts, ACSL3 shows divergent roles: high expression correlates with worse prognosis in melanoma, triple-negative breast cancer, and lung carcinoma 2, while in breast cancer it paradoxically suppresses progression by inhibiting β-oxidation and β-catenin-independent YES1/YAP1 signaling 6. In hepatocellular carcinoma, ACSL3 promotes POPC synthesis and PPARα pathway activation, accelerating lipid metabolism and tumor growth 7. ACSQL3 is regulated post-translationally; during renal ischemia-reperfusion injury, ANKRD1 promotes TRIM25-mediated K63-linked ubiquitination and degradation of ACSL3, amplifying ferroptosis and tissue damage 8. FXR activation upregulates ACSL3 as part of a ferroptosis-suppressive program 9, highlighting ACSL3's critical function in lipid peroxidation regulation across metabolic and pathological contexts.