Study on the Regulatory Mechanism of GLP-1 Receptor Agonist Liraglutide in Diabetic Corneal Epithelial Wound Healing

Purpose: The purpose of this study was to elucidate the effects and mechanisms of liraglutide in repairing diabetic corneal epithelial injury, explore its therapeutic advantages, and provide experimental evidence for clinical application. Methods: GLP-1R expression in mouse corneal epithelium was detected by Western blotting, qPCR, and immunofluorescence. Streptozotocin-induced diabetic mice and 30 mM high-glucose (HC) cell models were established. Epithelial wound healing, viability, proliferation, migration, and apoptosis were evaluated by fluorescein staining, TUNEL, CCK-8, EdU, and scratch assay. Bioinformatics was used to screen differentially expressed genes. Reactive oxygen species (ROS), redox indicators, and key proteins in Keap1-Nrf2-ARE, PI3K/Akt, and MAPK pathways were measured. PI3K inhibitors were applied to verify the pathway function, and macrophage polarization and recruitment were further assessed. Results: GLP-1R was mainly located in the deep basal cells of corneal epithelium. Liraglutide improved cell viability, promoted proliferation and migration, and inhibited apoptosis. It restored redox balance and alleviated oxidative stress via activating Nrf2/HO-1/NQO-1 pathway, and enhanced cell functions through PI3K/Akt pathway; these effects were abolished by PI3K inhibition. Moreover, liraglutide reduced aberrant macrophage infiltration, promoted anti-inflammatory macrophage polarization, and decreased pro-inflammatory factors, which was associated with MAPK pathway downregulation. Conclusions: Liraglutide exerts multi-mechanism protective effects on diabetic corneal epithelium. It regulates Nrf2 and PI3K/Akt pathways to attenuate oxidative stress and improve cell functions, and modulates macrophage polarization and recruitment via MAPK pathway to relieve inflammation, thereby promoting corneal epithelial injury repair.