METABOLIC REPROGRAMMING IN HEPATOCELLULAR CARCINOMA: TARGETING MITOCHONDRIAL BIOGENESIS

Abstract

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming, often driven by mitochondrial biogenesis. This study investigated the role of mitochondrial biogenesis in the metabolic adaptation of HCC cells, with a focus on its implications for tumor progression and therapeutic targeting. Gene expression analyses revealed significant upregulation of key mitochondrial regulators including PGC-1α, NRF1, and TFAM in HCC tissues compared to non-tumorous liver, indicating enhanced mitochondrial mass and biogenic activity. Metabolomic profiling showed elevated levels of lactate, pyruvate, and TCA cycle intermediates in HCC, reflecting a metabolic shift toward both glycolysis and oxidative phosphorylation. Mitochondrial DNA content and ATP production were markedly increased, alongside elevated reactive oxygen species (ROS), highlighting the hypermetabolic state of tumor cells. Public transcriptomic data (TCGA-LIHC) demonstrated that high expression of mitochondrial biogenesis genes correlated with improved overall survival, establishing their potential prognostic value. Functional assays revealed that pharmacological inhibition of mitochondrial biogenesis, especially through metformin and a B-raf inhibitor–diclofenac combination, led to a significant reduction in HCC cell viability. Pathway enrichment analysis identified oxidative phosphorylation and fatty acid oxidation as dominant metabolic programs in HCC. Collectively, the data affirm that mitochondrial biogenesis not only supports HCC metabolic plasticity and growth but also represents a promising therapeutic target. The study emphasizes the necessity of precise therapeutic modulation, given the fundamental role of mitochondria in normal cell function. These findings lay a foundation for developing mitochondria-targeted strategies aimed at selectively impairing cancer cell metabolism, potentially enhancing treatment outcomes in HCC patients.