Advances in mitophagy research in hepatocellular carcinoma: mechanisms and therapeutic implications

Mitophagy, a selective autophagic process crucial for mitochondrial quality control, plays a context-dependent dual role in hepatocellular carcinoma (HCC), functioning as both a tumor suppressor and a promoter of malignancy. This review provides a comprehensive analysis of the mechanistic landscape and therapeutic implications of mitophagy in HCC. We detail how mitophagy influences hepatocarcinogenesis, tumor progression, metabolic reprogramming, and the maintenance of liver cancer stem cells (LCSCs). Central to its function are two primary pathways: the ubiquitin-dependent PINK1/Parkin axis and receptor-mediated pathways such as FUNDC1 and BNIP3/NIX, each demonstrating scenario-specific outcomes that contribute to the complexity of HCC biology. A major focus is placed on mitophagy's significant role in fostering resistance to various therapies, including tyrosine kinase inhibitors (TKIs), chemotherapy, and radiotherapy, thereby presenting a formidable clinical challenge. In response, we critically evaluate emerging therapeutic strategies that target mitophagy. These approaches are strategically bifurcated: one aimed at inhibiting pro-survival mitophagy to sensitize tumors to cell death, and another designed to induce excessive, lethal mitophagy for direct cancer cell eradication. We further explore innovative frontiers that integrate mitophagy modulation with immunotherapy, metabolic intervention, and tumor microenvironment (TME) remodeling. This review underscores mitophagy as a pivotal yet complex therapeutic node in HCC. It concludes that a nuanced, context-dependent understanding of mitophagy's dual functions is essential for developing precise and effective treatment strategies to combat this aggressive cancer.