Mechanism of action of Yes-associated protein in the development and progression of hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is highly prevalent worldwide with a high mortality rate. Despite the continuous advances in current treatment methods such as surgery， targeted drugs， and immunotherapy， there is still a lack of significant improvement in the 5-year survival rate of patients due to strong tumor heterogeneity， high metastatic potential， and a high drug resistance rate. Therefore， it is urgently needed to identify new therapeutic targets. The aberrant activation of Yes-associated protein （YAP） is a pivotal hub for cell proliferation， metastasis， and immune evasion of HCC. This article systematically reviews the multiple regulatory mechanisms underlying YAP activation in HCC， including the promotion of YAP nuclear translocation by Hippo pathway inactivation， G protein-coupled receptor signal activation， and changes in mechanical stress of extracellular matrix. Meanwhile， it summarizes the synergistic crosstalk between YAP and non-classical pathways such as the Wnt pathway， as well as its specific role in remodeling the immune microenvironment and facilitating tumor immune escape by upregulating programmed death ligand 1. In addition， it reviews the development of new technologies such as YAP-TEAD inhibitors and proteolysis-targeting chimera and points out that interactions between the multiple regulatory mechanisms of YAP is a key contributor to tumor heterogeneity and therapeutic resistance. Future research should focus on developing novel inhibitors targeting the YAP regulatory network， designing combined therapy strategies， and establishing molecular biomarker detection systems， which may become pivotal directions for promoting precise treatment of HCC.