Ferroptosis is a novel form of iron-dependent, non-apoptotic cell death driven by lipid peroxidation, playing a crucial role in the development of hepatocellular carcinoma (HCC). Various clinical agents, such as sorafenib, have been found to induce ferroptosis and exhibit therapeutic effects by modulating key factors in the ferroptosis pathway. This review summarizes the prerequisites and defense systems for ferroptosis, the regulatory targets of drug-mediated ferroptosis in HCC, and the differences and connections between ferroptosis and other programmed cell deaths. The authors aim to provide a theoretical basis for understanding ferroptosis in HCC and to explore new and precise preventive and therapeutic measures for patients. Key points include the importance of ferroptosis in HCC, the metabolic processes involved, natural defense mechanisms, and the involvement of ferroptosis-regulated genes in HCC development. The review also discusses the challenges of drug resistance and the potential of combining ferroptosis induction with immunotherapy to enhance antitumor effects.Ferroptosis is a novel form of iron-dependent, non-apoptotic cell death driven by lipid peroxidation, playing a crucial role in the development of hepatocellular carcinoma (HCC). Various clinical agents, such as sorafenib, have been found to induce ferroptosis and exhibit therapeutic effects by modulating key factors in the ferroptosis pathway. This review summarizes the prerequisites and defense systems for ferroptosis, the regulatory targets of drug-mediated ferroptosis in HCC, and the differences and connections between ferroptosis and other programmed cell deaths. The authors aim to provide a theoretical basis for understanding ferroptosis in HCC and to explore new and precise preventive and therapeutic measures for patients. Key points include the importance of ferroptosis in HCC, the metabolic processes involved, natural defense mechanisms, and the involvement of ferroptosis-regulated genes in HCC development. The review also discusses the challenges of drug resistance and the potential of combining ferroptosis induction with immunotherapy to enhance antitumor effects.