The protective role of quercetin in cataract lenses and its mechanisms related to the hippo signaling pathway.

Purpose: To elucidate whether the quercetin mitigates cataract pathology by modulating the Hippo signaling pathway and to determine the functional consequences of Hippo activation or inhibition on lens protection and epithelial-cell proliferation.

Methods: A network-pharmacology strategy was first used to pinpoint cataract-related targets and their enriched pathways, nominating quercetin as the top Hippo-associated compound. In vivo, a UVB-induced cataract mouse model received quercetin with or without the Hippo activator α-hederin. Lens opacity, histopathology, oxidative stress parameters (MDA, GSH, SOD), and expression levels of Hippo signaling and proliferation/apoptosis markers were systematically evaluated. In vitro, H₂O₂-injured mouse lens epithelial cells (LECs) were treated analogously; proliferation was quantified by CCK-8, and pathway proteins by western blotting.

Results: Network analysis highlighted the Hippo pathway as the most significantly enriched cataract pathway, with quercetin showing the strongest Hippo-target overlap. In cataract mice, quercetin reduced lens opacification, restored histo-architecture, lowered MDA, and elevated GSH and SOD. Concomitantly, p-MST1, p-YAP and TAZ levels fell, whereas Ki-67 and BCL-2 rose and BAX and Cleaved Caspase-3 declined, indicating Hippo inactivation and enhanced epithelial survival. α-Hederin re-activated Hippo signaling, reversed quercetin's biochemical improvements and lens protection. Quercetin similarly promoted proliferation and inhibited Hippo signaling in H₂O₂-injured LECs, effects reversed by α-hederin.

Conclusion: Quercetin appears to alleviate lens damage and promote epithelial cell proliferation in cataracts, possibly through the modulation of the Hippo signaling pathway. Reactivation of this pathway seems to attenuate some of the protective effects, indicating that suppression of the Hippo pathway may contribute to these outcomes. These findings suggest that quercetin holds potential as a therapeutic agent for cataracts, although further research is required to fully elucidate its underlying mechanisms.