ACSL4 as a potential ferroptosis target in hepatocellular carcinoma: from mechanisms to implications

Ferroptosis is a recently identified form of cell death caused by iron-dependent peroxidation of lipids. Altered lipid metabolism plays a crucial role in determining the vulnerability of hepatocellular carcinoma (HCC) cells to ferroptosis. Targeting lipid-peroxidation-driven ferroptosis has been increasingly recognized as a promising strategy in cancer therapy. Long-chain acyl-CoA synthetase family member 4 (ACSL4) is one of the key drivers of the ferroptosis process. ACSL4 modifies the phospholipid makeup of cell membranes, controls steroid production, and maintains a balance in eicosanoid biosynthesis. Moreover, metabolic reprogramming driven by ACSL4, along with its role in antitumor immunity, has attracted considerable interest in the field of cancer biology. Here, we present a summary of the diagnostic role of ACSL4 in HCC and the functions of ACSL4 in HCC initiation, development, metastasis, tumor immunity, and therapy resistance. Moreover, several possible therapeutic strategies based on ACSL4-mediated ferroptosis are discussed. Research on the molecular mechanisms of ACSL4 is critical for the development of targeted therapies for HCC.