Mitochondrial dysfunction in hepatocellular carcinoma: Linking aging hallmarks to organelle dynamics, metabolism, and disease progression

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of hepatocellular carcinoma, driving metabolic reprogramming, oxidative stress, and genomic instability. This paper aims to define mitochondrial dysfunction as a central driver of hepatocellular carcinoma and identify mitochondrial pathways as targets for precision therapy. In hepatocellular carcinoma, aberrant mitochondrial dynamics marked by dysregulated fission and fusion processes promote the Warburg effect, a metabolic shift toward aerobic glycolysis over oxidative phosphorylation, even in oxygen-rich environments. This dysfunction is exacerbated by the accumulation of mitochondrial DNA mutations and increased production of reactive oxygen species, which promote tumorigenesis by inducing oncogenic mutations and disrupting cellular homeostasis. Risk factors such as chronic hepatitis B virus and hepatitis C virus, alcohol consumption, and obesity further compound mitochondrial impairment, creating a pro-tumorigenic microenvironment. Emerging therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, metabolic modulators, and small-molecule inhibitors, aim to restore mitochondrial function and mitigate oxidative damage. However, challenges persist due to the complexity of mitochondrial interactions within tumor ecosystems and debates over therapeutic efficacy. Advancing molecular insights into mitochondrial pathways such as dynamics, quality control, and immunometabolic crosstalk is critical for developing precision therapies to improve clinical outcomes in hepatocellular carcinoma.