Ferroptosis in Müller cells under hyperglycemia: mechanisms and therapeutic implications for diabetic retinopathy-associated optic neuroinflammation

Abstract

Background: Diabetic retinopathy (DR), traditionally considered a microvascular complication, is now increasingly recognized as a neurodegenerative and neuroinflammatory disorder. Among retinal glial cells, Müller cells are particularly susceptible to hyperglycemia-induced stress, playing a pivotal role in the progression of DR.

Objective: This review aims to systematically summarize the mechanisms by which high glucose induces ferroptosis in Müller cells and to explore the implications of ferroptotic damage for retinal neuroinflammation and blood-retinal barrier dysfunction in DR.

Methods: A comprehensive literature review was conducted focusing on recent experimental and translational studies related to ferroptosis pathways in diabetic retinal environments, particularly involving Müller cell pathology.

Results: Hyperglycemia promotes Müller cell ferroptosis via three major axes: 1. Iron metabolism dysregulation, including TfR1/DMT1 upregulation and autophagic degradation of ferritin (ferritinophagy); 2. Enhanced lipid peroxidation, driven by ACSL4 and lipoxygenase (LOX) activity; 3. Antioxidant system impairment, notably via suppression of the system Xc⁻/GPX4 axis. Ferroptosis in Müller cells contributes to neuroinflammation through the release of damage-associated molecular patterns (DAMPs), activation of retinal microglia, and disruption of the blood-retinal barrier.

Conclusion: Ferroptosis is a critical and previously underappreciated mechanism linking metabolic stress to neuroinflammation in DR. Targeting ferroptosis-via iron chelation, GPX4 restoration, or activation of the Nrf2 pathway-represents a promising therapeutic strategy to mitigate retinal neurodegeneration in diabetic patients.

Keywords: Diabetic retinopathy; Ferroptosis; High glucose; Lipid peroxidation; Müller cells; Optic neuroinflammation; Oxidative stress.