The Hippo-YAP/TAZ axis: A central signaling hub integrating diverse cues to regulate cellular senescence

Cellular senescence, an irreversible state of cell cycle arrest, has emerged as a critical contributor to tissue dysfunction and organismal aging, and is implicated in a range of pathological conditions including atherosclerosis, tissue fibrosis, neurodegenerative diseases, and cancer. Mounting evidence underscores the central role of the Hippo signaling pathway in regulating fundamental biological processes such as cell proliferation, senescence, and apoptosis in mammals. In its active state, the Hippo pathway facilitates the cytoplasmic sequestration of the transcriptional co-activators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), thereby promoting cellular senescence. Conversely, inhibition of Hippo signaling enables nuclear translocation of YAP/TAZ, which in turn drives the expression of genes associated with cell proliferation and tissue regeneration. Thus, the nucleo-cytoplasmic shuttling of YAP/TAZ serves as a pivotal determinant in the decision between cellular growth and senescence or apoptosis. It is noteworthy that YAP/TAZ deficiency can also trigger senescence through activation of the p16/p53 axis in the nucleus, representing an alternative senescence mechanism. This review provides a comprehensive overview of the canonical YAP-mediated pathways, with a focused discussion on how the Hippo pathway integrates diverse inputs, including oncogenic signals, mechanical cues, circadian rhythms, hypoxic conditions, and chronic inflammatory stimuli, to modulate the molecular and cellular processes underlying senescence.