Ferroptosis: A Novel Mechanism in Diabetic Keratopathy
Li Huang1,2, Wentao Liang3, Tanzeel Huma3
1Aier Eye Hospital, Jinan University, Guangzhou, Guangdong Province, China.
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.
Insights
Ferroptosis, an iron-dependent cell death, contributes to diabetic keratopathy (DK). Inhibiting ferroptosis with ferrostatin-1 (Fer-1) shows therapeutic potential for DK by reducing iron accumulation and oxidative stress.
Area of Science:
- Ophthalmology
- Cell Biology
- Pathology
Background:
- Diabetic keratopathy (DK) is a vision-impairing complication of diabetes mellitus.
- The underlying mechanisms of DK, particularly the role of cell death pathways, are not fully understood.
- Iron accumulation and oxidative stress are implicated in various diabetic complications.
Purpose of the Study:
- To investigate the role of ferroptosis, an iron-dependent cell death, in diabetic keratopathy (DK).
- To explore the therapeutic potential of ferroptosis inhibitors in treating DK.
- To integrate evidence from human tissues, animal models, and in vitro studies.
Main Methods:
- Examined iron accumulation in human diabetic and nondiabetic corneal tissues using Prussian blue staining.
- Assessed corneal iron staining and transferrin receptor 1 (TfR1) expression in a diabetic mouse model.
- Utilized primary human corneal epithelial cells exposed to high glucose to evaluate ferroptosis markers and the effect of ferrostatin-1 (Fer-1).
Main Results:
- Diabetic corneas (human and mouse) exhibited significantly increased iron staining, correlating with elevated TfR1 expression in mice.
- High glucose in vitro induced iron accumulation, increased oxidative stress (ROS, 4-hydroxynonenal), and altered antioxidant enzyme expression (decreased GPX4).
- Ferrostatin-1 (Fer-1) treatment reduced iron accumulation and ROS, restored GPX4, and improved cell viability, proliferation, and migration.
Conclusions:
- Ferroptosis is a key pathway implicated in the pathogenesis of diabetic keratopathy.
- High glucose levels in DK likely trigger ferroptosis by increasing cellular iron and impairing antioxidant defenses.
- Ferroptosis inhibitors, such as Fer-1, represent a promising therapeutic strategy for DK, warranting further investigation.
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