Advances in the role of mitochondrial homeostasis in hepatocellular carcinoma initiation and progression: Mechanisms and therapeutic opportunities

Hepatocellular carcinoma (HCC) is an aggressive malignancy characterized by profound metabolic reprogramming, mitochondrial dysfunction, and resistance to both conventional and immune-based therapies. Mitochondria play a central role in HCC development by coordinating bioenergetics, redox balance, mitochondrial dynamics, quality control, and immunometabolic signaling. Accumulating evidence indicates that disruption of mitochondrial fission, fusion, and mitophagy promotes tumor growth, metastasis, and therapeutic resistance through metabolic remodeling and adaptive stress responses. Enhanced mitochondrial fission, largely mediated by DRP1 and its associated adaptors, favors glycolytic reprogramming, reactive oxygen species (ROS) accumulation, and invasive behavior, whereas impaired fusion compromises oxidative phosphorylation efficiency. Alterations in mitochondrial DNA (mtDNA) integrity and nucleoid organization further exacerbate mitochondrial dysfunction. These changes can trigger inflammatory signaling through cytosolic mtDNA release and contribute to remodeling of the tumor microenvironment. Mitophagy exhibits context-dependent roles in HCC: it may suppress tumor initiation by removing damaged mitochondria, yet under stress conditions such as hypoxia or nutrient deprivation, it supports tumor survival and adaptation. Beyond tumor-intrinsic effects, mitochondrial metabolism plays a key role in shaping the tumor immune microenvironment. It regulates immunometabolism, antigen presentation, ROS signaling, and immune cell differentiation, thereby influencing immune evasion and responsiveness to immunotherapy. Collectively, mitochondrial pathways are emerging as actionable targets for overcoming immunosuppression and therapeutic resistance. This review integrates current knowledge on mitochondrial dynamics, metabolism, mtDNA regulation, mitophagy, and immunometabolic crosstalk in HCC, and discusses emerging strategies to exploit mitochondrial vulnerabilities for improved clinical outcomes.