PDZK1 Protects Against RPE Senescence by Targeting the 14‐3‐3ε‐mTOR Axis to Attenuate Early Diabetic Retinopathy

Abstract Diabetic retinopathy (DR) is the leading cause of blindness among working‐age adults, yet its pathogenesis remains incompletely understood. The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high‐glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14‐3‐3ε to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin‐induced DR mouse models, both PDZK1 overexpression‐mediated senescence inhibition and Nutlin‐3a‐induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early‐stage DR lesions. In summary, this study identifies a novel PDZK1‐14‐3‐3ε‐mTOR axis governing high‐glucose‐induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention.