Growth factor receptor-bound protein 2-mediated corneal epithelial injury drives depression-associated dry eye disease.

Depression is increasingly recognized as a comorbidity of dry eye disease (DED), yet its underlying mechanisms remain unclear. This study investigates the therapeutic effects of fluoxetine on depression-associated corneal injury and explores the molecular pathways involved. Chronic unpredictable mild stress (CUMS) mice received fluoxetine treatment. Behavioral tests, corneal wound healing, tear secretion, and 4D-DIA proteomics were performed. GRB2 expression was validated via immunohistochemistry, qRT-PCR, and western blot. Human corneal epithelial cells (hCECs) under hyperosmotic stress (450 mOsm) were transfected with GRB2 siRNA to assess oxidative stress, inflammation, and migration. Fluoxetine treatment significantly reduced depressive behaviors, accelerated corneal epithelial wound healing, and restored tear secretion. Proteomic analysis of corneal tissues revealed dysregulation of cytoskeletal and metabolic pathways in depressed mice, which fluoxetine partially reversed. GRB2 emerged as a critical protein, showing elevated expression in depressed mice and hyperosmolar-stressed hCECs. Silencing GRB2 in hCECs attenuated hyperosmolarity-induced oxidative stress, inflammation, and migration inhibition. Immunohistochemical and behavioral analyses confirmed GRB2's role in corneal epithelial thinning and depression-related DED pathology. These findings highlight GRB2 as a potential therapeutic target and underscore fluoxetine's dual efficacy in mitigating depressive symptoms and ocular surface damage. This study provides novel insights into the molecular interplay between depression and DED, advocating for integrated therapeutic strategies addressing both psychiatric and ophthalmic dimensions.