Ferroptosis: A Novel Mechanism in Diabetic Keratopathy

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.

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.

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.

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.