Ferroptosis and Iron Homeostasis in Retinal Diseases

Ferroptosis is a regulated form of cell death characterised by iron-dependent lipid peroxidation and distinct from apoptosis or necroptosis. In the retina, precise control of iron uptake, storage and export is essential to maintain photoreceptor and retinal pigment epithelium (RPE) integrity. Disruption of iron homeostasis leads to accumulation of ferrous iron, elevated reactive oxygen species and mitochondrial dysfunction, triggering ferroptosis in RPE cells, photoreceptors and retinal ganglion cells. Key molecular players include glutathione peroxidase 4 (GPX4), which reduces lipid hydroperoxides, ferroptosis suppressor protein 1 (FSP1), which regenerates coenzyme Q10, and the ferritinophagy receptor NCOA4, which liberates iron from ferritin. Hypoxia-inducible factors, the renin–angiotensin system and oxidative stress further modulate these pathways. Ferroptosis contributes to the pathology of age-related macular degeneration, diabetic retinopathy and glaucoma, while iron deficiency from chelation therapy can paradoxically induce RPE atrophy through HIF2α-mediated mitochondrial impairment. Therapeutic strategies aim to rebalance iron levels with chelators, bolster antioxidant defences via glutathione precursors or coenzyme Q10, and inhibit ferroptosis using small-molecule inhibitors or metabolic modulators.

Research from Nature Portfolio

Studies have shown that retinal iron overload exacerbates neurovascular dysfunction in diabetic retinopathy. In mouse models of type 1 and type 2 diabetes, elevated iron deposition correlated with increased neuronal cell death, vascular abnormalities and breakdown of the blood–retinal barrier. Genetic iron overload further intensified these lesions and upregulated retinal renin expression via the succinate receptor GPR91, linking iron dysregulation to activation of the renin–angiotensin system. This work identifies a novel iron-renin axis in diabetic retinopathy and suggests that targeting iron homeostasis alongside renin–angiotensin modulation may offer therapeutic benefit.

Ferroptosis and Iron Homeostasis in Retinal Diseases publication trend

The graph below shows the total number of articles in ferroptosis and iron homeostasis in retinal diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A form of regulated cell death driven by iron-catalysed lipid peroxidation.

Ferritinophagy: Autophagic degradation of ferritin via NCOA4, releasing iron into the labile pool.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that detoxifies lipid hydroperoxides to prevent ferroptosis.

Ferroptosis suppressor protein 1 (FSP1): An enzyme reducing coenzyme Q10 to inhibit lipid peroxidation independently of GPX4.

Fenton reaction: Chemical reaction where ferrous iron converts hydrogen peroxide into hydroxyl radicals, driving oxidative damage.

Renin–angiotensin system: Hormonal cascade regulating vascular tone and permeability, implicated in diabetic retinal pathology.

References

1. HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy. EMBO Molecular Medicine (2023).
2. Iron Overload Accelerates the Progression of Diabetic Retinopathy in Association with Increased Retinal Renin Expression. Scientific Reports (2018).
3. Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction. Cell Death & Disease (2022).
4. Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma. Cell Death & Differentiation (2022).
5. Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis. Cell Death & Disease (2022).