Ferroptosis regulatory networks as therapeutic sensitizers in combination therapy for hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and multidrug resistance remains a major barrier to effective treatment. Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxide accumulation, has emerged as a potential therapeutic strategy for HCC because it may bypass apoptosis-related resistance mechanisms. The present narrative review summarizes current evidence on ferroptosis-mediated sensitization mechanisms in combination therapy for HCC, focusing on core regulatory networks, including glutathione peroxidase 4, System Xc- and iron metabolism pathways, and their interactions with key signaling pathways, such as activating transcription factor 4/signal transducer and activator of transcription 3, p53 and Wnt/β-catenin. The current review also discusses the synergistic effects and molecular mechanisms of ferroptosis inducers combined with targeted therapy, chemotherapy and immunotherapy. Furthermore, the potential value of ferroptosis-related biomarkers for predicting treatment response and prognosis is evaluated, and unresolved mechanistic questions and barriers to clinical translation are highlighted. Finally, the present review outlines future research directions, including the development of targeted nanodelivery systems and biomarker-based clinical trials, to support more precise ferroptosis-based combination strategies for HCC.