Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies

Globally, liver cancer is reported to be the third leading cause of cancer-related mortality. The most common type of these cancers is hepatocellular carcinoma (HCC). Current preventive strategies, including lifestyle modifications, antiviral therapies, and surveillance, are limited in their effectiveness. Mitochondria play critical roles in regulating cellular metabolism, oxidative stress, and apoptosis. Mitochondrial dysfunction can accelerate HCC progression, particularly in patients with liver diseases such as metabolic-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this review, we discuss the mechanisms of mitochondrial dysfunction in HCC from a molecular point of view, including oxidative stress, mitophagy dysregulation, mitochondrial dynamics dysregulation, and mitochondrial DNA (mtDNA)-mediated dysregulation of innate immune responses. Additionally, we explore molecular-targeted therapies aimed at restoring mitochondrial function. Critical approaches include targeting reactive oxygen species pathways through agents such as iridium (III) complexes and Mito Rh S, which induce cancer cell death through apoptosis and ferroptosis. Other compounds, including dehydrocrenatidine, enhance oxidative phosphorylation and promote apoptosis. Inhibitors of dynamin-related protein 1 (Drp1) target mitochondrial fission to reduce tumor growth. Furthermore, mitophagy modulators, such as SIRT1 activators, improve mitochondrial quality control, minimize the negative effects of oxidative stress, and reduce cancer development. Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease.