Mitochondrial dynamics imbalance in hepatocellular carcinoma: from molecular mechanisms to new strategies for...

Hepatocellular carcinoma (HCC), a malignancy with high global mortality, exhibits a close association with mitochondrial dynamic imbalance. Mitochondria maintain cellular homeostasis through a dynamic equilibrium of fission and fusion, and dysregulation of this process can trigger metabolic reprogramming, oxidative stress, and dysregulation of multiple modes of cell death, ultimately driving HCC progression. This review systematically elucidates the molecular mechanisms and therapeutic targets associated with mitochondrial dynamic imbalance in HCC. It begins by analyzing the structure and functional characteristics of mitochondria, outlining the universal impact of their fission-fusion regulatory network on cancer biology. Subsequently, it focuses on HCC-specific pathological mechanisms, revealing how mitochondrial dynamic imbalance reshapes the tumor microenvironment via the Warburg effect, lipotoxicity, and reactive oxygen species (ROS) burst. A key emphasis is placed on the role of mitochondrial dysfunction in regulating multiple modes of cell death, including apoptosis, ferroptosis, pyroptosis, autophagy, and the emerging mechanism of cuproptosis. The link between cuproptosis and mitochondrial copper accumulation, lipoylated protein aggregation, and metabolic collapse provides a novel perspective for HCC therapy. Finally, the review critically evaluates therapeutic strategies targeting mitochondrial dynamics, discussing the translational potential of DRP1 inhibitors (e.g., Mdivi-1), mitophagy activators (e.g., rapamycin), and copper chelators (e.g., tetrathiomolybdate). Future directions, such as mitochondrial-targeted nanodelivery systems and multi-target combination therapies, are also explored. This comprehensive review aims to provide a theoretical foundation and innovative insights for understanding the pathogenesis and advancing precision therapy in HCC.