The Hippo Signaling Pathway Regulates Corneal Endothelial Regeneration

Abstract Corneal endothelial cells (CECs) have limited regeneration capacity in primates while display a potent restorative capability in some species such as rodents after wounding. The mechanism which determines the regenerative capability of CECs remains poorly understood. Here, we identify that the Hippo signaling pathway is inhibited and the downstream effector YAP is activated during CEC wound healing in rabbit and mouse. Knockdown of Yap1 and pharmacological inhibition of YAP suppresses CECs wound healing in rodents in both in vitro and in vivo models. XMU-MP-1, a specific small molecular inhibitor for Hippo signaling pathway, can promote the corneal endothelial regeneration in rodents and corneal endothelial proliferation in cultured primate CECs, as well as in vivo non-human primate CEC wounding model. These findings suggest that Hippo pathway serves as a conserved signal to regulate corneal endothelial regeneration among various species, providing a novel target for non-invasive treatment of corneal endothelium decompensation. Competing Interest Statement The authors have declared no competing interest. Footnotes Funding: This study was supported in part by the National Natural Science Foundation of China (82471047, 81970773, 82401223), China Post-doctoral science foundation (2024M751351, 2023M741610, BX20240154), Natural Science Foundation of Hunan Province, China (2025JJ90130), Natural Science Foundation of Hunan Province, China (2024JJ6403). The sequencing-related data removed from the Figure 1; Figure 5 and Figure 6 added; Figure 4 revised; 2 authors added; Supplemental files updated; Layout format updated.