Inhibition of YAP signaling suppresses fibrosis and posterior capsular opacification in preclinical models of cataract surgery

PURPOSE: A frequent fibrotic sequela following cataract intervention is posterior capsular opacification (PCO), which is primarily triggered by lens epithelial cells (LECs) undergoing epithelial-mesenchymal transition (EMT). The objective of this research was to examine how yes-associated protein (YAP) modulates EMT in LECs and to determine the contribution of connective tissue growth factor (CTGF) to this regulatory axis. METHODS: A simulated cataract surgery model was established in C57BL/6 mice to examine YAP expression during postoperative EMT in lens epithelium. EMT was induced in human SRA01/04 LECs and mouse primary lens epithelial explants using transforming growth factor-β1 (TGF-β1). YAP expression and activity were modulated by lentiviral-mediated knockdown or overexpression and pharmacological inhibition using verteporfin. To evaluate the expression of YAP-related target genes and EMT markers, techniques including real-time PCR, Western blot, and immunofluorescence were employed. The role of CTGF was evaluated using a neutralizing antibody. RESULTS: YAP expression was increased in LECs following simulated cataract surgery and throughout the process of TGF-β1-mediated EMT within cultured cells. Suppression of YAP expression or activity significantly attenuated EMT, characterized by the downregulation of Fibronectin and α-SMA alongside the maintenance of epithelial markers. Conversely, YAP overexpression promoted EMT-associated molecular changes. Neutralization of CTGF partially reversed YAP-induced EMT, indicating CTGF contributes to YAP-dependent EMT regulation. CONCLUSIONS: The progression of EMT in LECs is driven by YAP activation, a process that occurs, to a certain extent, via the enhancement of CTGF expression. Targeting YAP signaling may represent a potential therapeutic strategy for preventing EMT-driven PCO following cataract surgery.