Ferroptosis: A Novel Mechanism in Diabetic Keratopathy.

Abstract

PURPOSE: To investigate whether ferroptosis, an iron-dependent form of cell death, contributes to diabetic keratopathy (DK) by integrating evidence from human tissues, a diabetic mouse model, and in vitro studies and to explore the potential of ferroptosis inhibitor as a therapeutic strategy. METHODS: Human diabetic and nondiabetic corneal biopsy tissues were examined for iron accumulation using Prussian blue staining. In a streptozotocin-induced diabetic mouse model, corneal iron staining and transferrin receptor 1 (TfR1) expression were assessed. Primary human corneal epithelial cells were exposed to high glucose for 3 days to evaluate iron staining, 4-hydroxynonenal and reactive oxygen species production, and protein expression of TfR1 and glutathione peroxidase 4 (GPX4). To probe the mechanism, human corneal epithelial cells were treated with the ferroptosis inhibitor ferrostatin-1 (Fer-1) and assessed for iron, ROS, proliferation, migration, protein expression, and cell viability. RESULTS: Diabetic human and mouse corneas showed significantly increased iron staining. In mice, the staining correlated with elevated TfR1 expression. In vitro, high glucose induced iron accumulation, increased 4-hydroxynonenal and ROS, and altered protein expression (increased TfR1 and decreased GPX4). Fer-1 reduced high glucose-induced iron accumulation and ROS, restored GPX4, and improved proliferation, migration, and viability; TfR1 levels remained unchanged. CONCLUSIONS: These findings suggest that ferroptosis plays an important role in DK. High glucose triggers this pathway by increasing iron and disrupting antioxidant defense. Targeting ferroptosis with inhibitors such as Fer-1 may have potential relevance in DK, but further studies are needed to clarify its therapeutic value.