Exp Eye Res. 2025 Dec 22;264:110820. doi: 10.1016/j.exer.2025.110820. Online ahead of print.
ABSTRACT
BACKGROUND: Diabetic keratopathy (DK) is a prevalent yet often overlooked complication of diabetes, marked by delayed corneal epithelial repair and impaired nerve regeneration. Despite its clinical significance, effective pharmacological interventions are still lacking, largely due to the limited understanding of its underlying molecular mechanisms.
METHODS: Type 1 diabetic mice were used to evaluate corneal wound closure, nerve density, and oxidative stress after modulation of DJ-1 expression by plasmid transfection. Human corneal epithelial cells (HCECs) cultured under high-glucose conditions were assessed for mitochondrial membrane potential (JC-1 staining), intracellular reactive oxygen species (DCFH-DA staining), and cell proliferation (Ki67 staining). DJ-1 expression was enhanced by agonists, while ERK1/2 signaling was selectively inhibited. Apoptosis was detected by TUNEL staining, protein levels were analyzed by Western blotting, and mitochondrial morphology was examined by MitoTracker staining.
RESULTS: High glucose disrupted mitochondrial function, elevated ROS, and reduced HCEC viability. DJ-1 restoration enhanced p-ERK1/2 signaling, attenuated oxidative stress, and promoted epithelial repair and nerve regeneration in diabetic mice. In vitro, DJ-1 overexpression preserved mitochondrial integrity, upregulated antioxidant defenses, and facilitated proliferation and migration, whereas ERK1/2 inhibition abolished these protective effects. Mechanistically, DJ-1 directly interacted with ERK1/2 and promoted nuclear translocation of p-ERK1/2, thereby activating antioxidant pathways.
CONCLUSION: The DJ-1/ERK1/2 signaling axis plays a pivotal role in maintaining corneal epithelial and neural homeostasis in diabetes. DJ-1 targeting may represent a promising therapeutic strategy for DK.
PMID:41435751 | DOI:10.1016/j.exer.2025.110820