The Hippo Pathway in Intestinal Regeneration, Fetal Reprogramming, and Tumorigenesis

The Hippo signaling pathway, first identified in Drosophila, is a conserved regulator of organ size and tissue homeostasis that balances proliferation and apoptosis. In mammals, its core kinases mammalian Sterile 20-like kinases 1 and 2 (MST1/2) and large tumor suppressor kinases 1 and 2 (LATS1/2) restrict the transcriptional coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), whose nuclear translocation drives cell proliferation and survival. In the intestine, YAP/TAZ activity is normally repressed to maintain homeostasis, but transient activation following injury promotes regeneration. Injury-induced YAP signaling triggers a regenerative transcriptional program marked by fetal gene re-expression and the emergence of Clusterin (Clu)-positive revival stem cells (revSCs), which restore leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5⁺) intestinal stem cells and epithelial integrity. Cross talk between Hippo, Wingless-related integration site (WNT), transforming growth factor β (TGF-β), and p53 signaling orchestrates this dynamic repair process, with precise temporal control of YAP essential for successful regeneration. Dysregulation of these interactions contributes to colorectal cancer tumorigenesis, highlighting the Hippo pathway as a central hub linking intestinal homeostasis, regeneration, and cancer.