Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy

Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.