Metabolic stress-induced dysregulation of the Hippo signaling pathway inhibits the occurrence of hepatocarcinoma

Liver fibrosis is the natural stress response of the liver to injury and a critical intermediate stage in the progression of most liver diseases. Here, we first demonstrated <i>via</i> a retrospective clinical study that the incidence of advanced hepatocellular carcinoma (HCC) was significantly higher in patients infected with hepatitis B virus (HBV) than in those with hepatolenticular degeneration (HLD). Further analyses involving micro RNA (miRNA) and proteomics were conducted to investigate the distinct mechanisms underlying liver fibrosis induced by HBV and HLD. Results showed significant changes in metabolic pathways and molecules, especially in AMP-activated protein kinase (AMPK) and Hippo signaling pathways, which play crucial roles in cellular glucose and lipid metabolism. Characteristic of HLD is a mutation/deletion in the ATPase Copper Transporting Beta (ATP7B) gene. Subsequent studies indicated that the knockdown or overexpression of ATP7B mutants activates the AMPK and Hippo signaling pathways, resulting in the inhibition of proliferation and transformation of HCC cells. AMPK phosphorylation indicates the presence of metabolic stress. Thus, this finding might partly explain why patients with HLD-related liver fibrosis are more likely to develop liver failure rather than HCC, providing new insights into the intricate mechanisms linking metabolic orchestration and tumor development.