USP7-DDX5-FASN axis drives fatty acid metabolism and supports hepatocellular carcinoma progression

Lipid metabolism plays a critical role in meeting the biosynthetic demands of rapidly proliferating tumor cells and is a major driver in the development of hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying this process remain unclear. In this study, we identified DEAD box protein 5 (DDX5) as a key regulator of fatty acid synthesis in HCC. Analysis of multiple HCC cohorts revealed a marked elevation in DDX5 expression, which is closely correlated with poorer clinical outcomes. Functional studies demonstrated that DDX5 facilitates HCC cell proliferation, enhances colony formation, and promotes fatty acid synthesis through the upregulation of fatty acid synthetase (FASN). In vivo studies showed that inhibition of DDX5 effectively suppressed tumor growth. Further investigation identified an interaction between DDX5 and ubiquitin-specific peptidase 7 (USP7), whereby USP7 stabilizes DDX5 by removing ubiquitin chains through deubiquitination. Collectively, these findings highlight the USP7-DDX5-FASN axis as a critical regulator of fatty acid metabolism in HCC progression, offering potential avenues for therapeutic intervention.