YAP-induced MAML1 cooperates with STAT3 to drive hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a major liver malignancy and a leading cause of cancer-related mortality worldwide. Given its rising incidence and poor prognosis, there is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop novel targeted therapies. In this study, we identify MAML1 as a key contributor to HCC development. Elevated MAML1 expression strongly correlated with disease severity, whereas its knockdown suppressed HCC progression. Functionally, MAML1 promoted tumor malignancy by regulating STAT3 activity. Mechanistically, MAML1 interacted with STAT3 and enhanced its acetylation in a p300-dependent manner. Inhibition of STAT3 with a specific inhibitor attenuated MAML1-driven HCC progression. Furthermore, signaling pathway analyses revealed that YAP is the principal transcription factor regulating MAML1 expression by directly binding its promoter. Importantly, depletion of MAML1 diminished YAP-induced HCC malignancy and STAT3 activation, suggesting that YAP, MAML1, and STAT3 form a coordinated signaling axis that drives HCC progression. Collectively, these findings uncover a novel MAML1-centered signaling pathway in HCC and provide a compelling rationale for the development of MAML1-targeted clinical strategies for disease management.