BACKGROUND: Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.
OBJECTIVE: This review comprehensively elucidates the molecular mechanisms governing these PCD pathways, their dysregulation in HCC, and the resulting therapeutic opportunities.
METHODS: We systematically analyzed current literature to detail the core regulators of each PCD pathway, summarize how HCC cells evade them, and evaluate preclinical and clinical strategies for therapeutic targeting.
KEY FINDINGS: HCC cells hijack multiple mechanisms to suppress apoptosis and divert necroptosis. Pyroptosis exhibits a dual role, acting as a tumor suppressor but also contributing to an immunosuppressive microenvironment in established tumors. Autophagy serves a context-dependent function, preventing tumor initiation but sustaining advanced tumors. Promisingly, preclinical studies demonstrate that resensitizing HCC cells to PCD, particularly through combination therapies, can overcome resistance. Early-phase clinical trials targeting these pathways, especially with autophagy inhibitors, have shown manageable safety profiles and hints of efficacy, though larger trials are needed.
CONCLUSION: The precise modulation of PCD pathways represents a promising frontier in HCC therapy. Future efforts must focus on patient stratification, biomarker development, and rational combination strategies that exploit the crosstalk between different PCD modalities to improve clinical outcomes.
