An updated review of YAP: A promising therapeutic target against cardiac aging?

The transcriptional co-activator Yes-associated protein (YAP) functions as a downstream effector of the Hippo signaling pathway and plays a crucial role in cardiomyocyte survival. In its non-phosphorylated activated state, YAP binds to transcription factors, activating the transcription of downstream target genes. It also regulates cell proliferation and survival by selectively binding to enhancers and activating target genes. However, the upregulation of the Hippo pathway in human heart failure inhibits cardiac regeneration and disrupts astrogenesis, thus preventing the nuclear translocation of YAP. Existing literature indicates that the Hippo/YAP axis contributes to inflammation and fibrosis, potentially playing a role in the development of cardiac, vascular and renal injuries. Moreover, it is a key mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Given these insights, can we harness YAP's regenerative potential in a targeted manner? In this review, we provide a detailed discussion of the Hippo signaling pathway and consolidate concepts for the development and intervention of cardiac anti-aging drugs to leverage YAP signaling as a pivotal target.