Dry eye disease (DED) is a multifactorial ocular surface disorder for which effective therapeutic options remain limited. This study aimed to investigate the therapeutic effects of naringin (NAR) in DED and elucidate its underlying mechanisms. DED was induced by topical administration of 0.075% BAC twice daily for 7 days. During days 8-14, BAC administration was continued while mice received NAR eye drops Corneal epithelial integrity and tear secretion were evaluated using corneal fluorescein sodium staining and the phenol red cotton thread test, respectively. In parallel, an in vitro hyperosmotic stress model was constructed by exposing human corneal epithelial cells to hyperosmotic sodium chloride medium (90 mM). Inflammation, oxidative stress, apoptosis, and autophagy-related phenotypes and mechanisms were analyzed using real-time quantitative PCR, Western blot, flow cytometry, and immunofluorescence. NAR eye drops significantly alleviated ocular surface damage in DED mice, enhanced tear secretion, reduced corneal inflammatory factor expression, and increased conjunctival goblet cell density. Furthermore, NAR attenuated oxidative stress and apoptosis through the promotion of autophagic flux. Mechanistic investigations revealed that NAR downregulated the PI3K/AKT/mTOR signaling pathway, thereby enhancing autophagic flux, and that its anti-inflammatory and antioxidant effects are closely associated with the inhibition of this pathway. Collectively, these findings suggest that NAR represents a promising therapeutic candidate for DED, with its beneficial effects mediated through enhancing autophagic flux via the PI3K/AKT/mTOR pathway, leading to the alleviation of oxidative stress and ocular surface inflammation.
