Targeting YAP: mechanistic breakthroughs and therapeutic prospects in reversing organ fibrosis

Fibrosis, a critical global health challenge, is primarily characterized by pathological scar formation due to an imbalance in tissue injury repair mechanisms, ultimately leading to progressive organ dysfunction. Notably, the Yes-associated protein (YAP), a central effector molecule in the Hippo signaling pathway, serves as a pivotal molecular regulator across fibrotic processes in multiple organs. Aberrant YAP activation is a hallmark of fibrosis in multiple organs, including the liver, kidney, heart, and lung, where it drives pro-fibrotic gene expression. Although basic research has highlighted YAP's essential role in fibrotic diseases, translating these insights into clinical applications remains complex. The current repertoire of targeted therapeutic options for fibrosis is restricted, further complicated by variations in tissue-specific responses to YAP modulation. This highlights the urgent need for a thorough analysis of the YAP regulatory network. In this review, we analyze the YAP protein interaction network to clarify the dynamic regulation of its nuclear-cytoplasmic trafficking. Furthermore, we explore the distinct signaling characteristics of YAP during organ fibrosis, summarize recent developments in anti-fibrotic strategies targeting YAP, and assess the translational potential of intervening in YAP and its upstream and downstream pathways for effective anti-fibrotic therapy.