Speaker
Description
Background & Question: Metastasis is the primary cause of death in hepatocellular carcinoma (HCC), a highly metabolic malignancy. Although bile acids are recognized as pleiotropic signaling metabolites, most studies have focused on total bile acid pools and their canonical nuclear receptors, leaving the functional contributions of individual bile acid species largely unexplored.
Results & Conclusion: We identified glycocholic acid (GCA) as a metastasis-promoting bile acid that was markedly elevated in human HCC tissues, correlating with metastatic disease and short overall survival. In orthotopic and spontaneous mouse HCC models, we showed that increasing GCA levels, exogenously or via hepatocyte-specific BAAT expression to recapitulate endogenous GCA accumulation, promoted intrahepatic and pulmonary metastasis without affecting primary tumor growth. Mechanistically, GCA drove metastatic dissemination by enhancing mitochondrial biogenesis and activity. GCA-treated cells exhibited increased mitochondrial respiration and ATP production, alongside elevated mitochondrial mass and number per cell. Critically, pharmacological inhibition of mitochondrial respiration with oligomycin A abolished GCA-induced tumor cell migration, confirming that enhanced mitochondrial function is not merely correlative but functionally required for its pro-metastatic effects.
Significance: Our study demonstrates GCA as a functional metabolic driver of HCC metastasis, uncovering a previously unrecognized GCA-mitochondria metabolic axis, positioning it as a promising therapeutic target for metabolic intervention in advanced HCC.
Key words: Hepatocellular carcinoma; Glycocholic Acid; Metastasis; Mitochondria.
