ECM stiffness governs endothelial barrier integrity through YAP-mediated stabilization of ZO-1

In this study, the key role of YAP-ZO-1 mechanical transduction axis in maintaining endothelial barrier function was revealed for the first time through adjustable stiffness hydrogel, animal model and computational simulation. We found that matrix stiffness synergistically regulates YAP activity through the FAK and Hippo pathways, thereby stabilizing ZO-1 protein through non transcriptional mechanisms and preventing its ubiquitination degradation. The study provides new therapeutic targets for barrier dysfunction related diseases, such as corneal endothelial decompensation.