RORA Targeting PRNP Modulates Age‐Related Cataract via Activation Oxidative Injury‐Induced Cellular Senescence and Apoptosis of Lens Epithelial Cells

Age-related cataract (ARC) is a severe vision-impairing disorder primarily caused by oxidative stress-induced senescence and apoptosis of lens epithelial cells (LECs). In this study, a sodium selenite-induced oxidative stress cataract model in neonatal rats was established to simulate the pathological progression of ARC. We found that retinoic acid receptor-related orphan receptor α (RORA) exacerbates cellular senescence and oxidative damage by targeting prion protein (PRNP), and its small-molecule inhibitor SR3335 exhibits therapeutic potential in regulating ARC progression. In vitro experiments showed that inhibiting RORA significantly alleviated cellular senescence, enhanced the anti-apoptotic capacity of LECs, and improved their resistance to oxidative stress, whereas activating RORA exerted opposite effects. In vivo, intravitreal injection of recombinant PRNP protein was demonstrated to abrogate the protective effect of RORA silencing, thereby exacerbating the progression of ARC. Mechanistically, RNA sequencing and dual-luciferase reporter assay revealed that RORA binds to its downstream target PRNP. RORA targets PRNP to regulate the p53/p21/Bax signaling pathway, thereby suppressing both cellular senescence and apoptosis. These findings highlight the critical role of the transcription factor RORA in ARC development by modulating oxidative stress injury, apoptosis, and senescence in LECs. The identification of PRNP as a downstream target of RORA may provide a novel dual-target strategy for ARC treatment.