Ferroptosis in Retinal Disease: Mechanisms, Evidence, and Therapeutic Implications

Abstract

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death characterized by accumulation of lipid hydroperoxides and failure of antioxidant defenses, particularly glutathione peroxidase 4 (GPX4).(1–3) Initially described in cancer biology, ferroptosis is now recognized as an important contributor to multiple ocular diseases, including age-related macular degeneration (AMD), retinal ischemia–reperfusion injury, diabetic retinopathy, glaucoma, and retinoblastoma.(1,4–7) The retina is especially vulnerable to ferroptotic damage due to its high polyunsaturated lipid content, intense metabolic activity, and exposure to visible light and oxygen.(5,8) Dysregulated iron homeostasis, mitochondrial dysfunction, chronic oxidative stress, and inflammatory signaling combine to favour ferroptosis in retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells.(4–6,9)

Experimental models demonstrate that iron overload, inhibition of the cystine–glutamate antiporter system Xc−, or pharmacologic GPX4 inactivation induce ferroptotic death of retinal cells, while ferroptosis inhibitors such as ferrostatin‑1 and iron chelators mitigate retinal degeneration.(6,9–12) Hypoxia and age-related alterations in the outer blood–retina barrier enhance susceptibility of RPE cells to ferroptosis through increased labile iron and Fenton chemistry.(9,13) In AMD models, mitochondrial dysfunction and disturbed lipid metabolism amplify ferroptotic pathways, suggesting a mechanistic link between ferroptosis and geographic atrophy progression.(5,8,14) Clinical evidence of retinal iron accumulation in AMD and hereditary iron overload disorders further supports this association.(8,15)

Therapeutic strategies targeting ferroptosis in retinal disease include iron chelation, upregulation of GPX4 and glutathione synthesis, activation of parallel antioxidant systems such as the FSP1–CoQ10–NAD(P)H axis, and modulation of ferroptosis-related signalling pathways.(1,4,10,11) Several small molecules and biologics that modulate these pathways have shown benefit in preclinical models of retinal ischemia, AMD, and diabetic retinopathy.(6,10,12,14) However, translation to clinical practice remains at an early stage, and the challenge of selectively modulating ferroptosis without impairing physiological iron-dependent processes is substantial. This review summarizes the molecular basis of ferroptosis, its involvement across major retinal pathologies, and current progress toward ferroptosis-targeted therapies.

Introduction

Ferroptosis was described in 2012 as a regulated cell death modality distinct from apoptosis, necroptosis, and autophagy, driven by iron-dependent peroxidation of polyunsaturated phospholipids in cellular membranes.(2,3) Morphologically, ferroptotic cells exhibit shrunken mitochondria with condensed membrane densities and reduced or absent cristae, while nuclear morphology remains relatively preserved.(2,3) Biochemically, ferroptosis is characterized by accumulation of reactive oxygen species (ROS) in phospholipids, depletion of glutathione (GSH), and impaired activity of GPX4, a selenoenzyme that detoxifies lipid hydroperoxides.(2,3,10)

The retina is highly susceptible to ferroptosis because it combines high oxygen consumption, abundant mitochondria, and a high content of polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid in photoreceptor outer segments.(5,8) The RPE–choriocapillaris complex also manages substantial iron flux, and age-related changes in iron handling and antioxidant capacity can shift the balance toward oxidative damage.(8,9,15) Systematic reviews and experimental studies now highlight ferroptosis as a convergent mechanism underlying RPE degeneration, photoreceptor loss, and retinal ganglion cell death in diverse retinal disorders.(1,4,6,7,9–11)

This article outlines the core molecular machinery of ferroptosis and how it operates in retinal cells, reviews evidence for ferroptosis in major retinal diseases with emphasis on AMD, and discusses the emerging therapeutic landscape of ferroptosis-targeted interventions.

Mechanistic Basis of Ferroptosis in the Retina

Iron Homeostasis and the Fenton Reaction

Cellular iron homeostasis is tightly regulated through coordinated uptake, storage, utilization, and export.(8,15) Transferrin receptor 1 mediates uptake of transferrin-bound Fe³⁺, which is reduced to Fe²⁺ and contributes to the cytosolic labile iron pool.(8) Excess iron is sequestered in ferritin or exported via ferroportin. Expansion of the labile iron pool facilitates Fenton reactions, in which Fe²⁺ catalyses conversion of hydrogen peroxide to highly reactive hydroxyl radicals, driving oxidative damage.(8,13,15)

In the retina, iron accumulation has been observed in RPE, photoreceptors, and Bruch’s membrane of AMD donor eyes and in animal models with genetic or dietary iron overload.(8,15) Iron-catalysed ROS promote peroxidation of PUFA-rich membranes in photoreceptor outer segments and RPE, triggering ferroptosis when antioxidant defences fail.(8,14–16) Ferritinophagy, an autophagy-dependent process that degrades ferritin and releases stored iron, further increases labile iron and can promote ferroptosis in ocular tissues.(1,4)

Lipid Peroxidation and Polyunsaturated Phospholipids

A central hallmark of ferroptosis is peroxidation of membrane phospholipids enriched in PUFAs such as arachidonic and adrenic acid.(2,3,10) In retinal cells, the high abundance of PUFAs in outer segment and RPE membranes creates a dense substrate for lipid peroxidation.(5,8) Enzymatic pathways involving acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) esterify PUFAs into phosphatidylethanolamines (PEs), which can be oxidized by lipoxygenases and non-enzymatic ROS-mediated reactions.(2,3,10)

Oxidized PE species such as 15-hydroperoxy-eicosatetraenoyl-PE accumulate during ferroptosis and act as biochemical markers of this process.(2,3) In human RPE cell models, oxidative stressors and iron overload increase lipid peroxidation and cell death, which is attenuated by ferroptosis inhibitors that block PUFA incorporation or scavenge lipid radicals.(6,11,16)

Glutathione, GPX4, and the System Xc− Antiporter

The major intracellular defence against lipid peroxidation is the GSH–GPX4 axis.(2,3,10) System Xc−, a cystine–glutamate antiporter composed of SLC7A11 and SLC3A2, imports cystine in exchange for glutamate. Cystine is reduced to cysteine, a rate-limiting precursor for GSH synthesis.(2,3) GPX4 uses GSH to reduce lipid hydroperoxides to non-toxic alcohols, thereby maintaining membrane integrity.

Inhibition of system Xc− (for example by erastin), depletion of GSH, or direct inactivation of GPX4 (for example by RSL3) leads to uncontrolled lipid peroxidation and ferroptotic cell death.(2,3,10) Human RPE cells exposed to tert‑butyl hydroperoxide or other oxidants exhibit glutathione depletion, lipid ROS accumulation, and iron-dependent death that is rescued by ferrostatin‑1 or deferoxamine, confirming ferroptosis as a key pathway in oxidatively stressed RPE.(6,11)

Parallel Antioxidant Systems and Regulatory Pathways

Not all ferroptosis defence depends on GPX4. The NAD(P)H-dependent oxidoreductase FSP1 (AIFM2) reduces coenzyme Q10 (CoQ10) in the plasma membrane, forming a FSP1–CoQ10–NAD(P)H axis that suppresses lipid peroxidation in parallel with GPX4.(1,10) This system appears active in RPE and retinal neurons and may be therapeutically exploitable.(1,4)

Additional regulatory mechanisms include the GCH1–BH4–DHFR axis, nuclear factor erythroid 2-related factor 2 (Nrf2)–mediated antioxidant responses, and transcriptional control by p53 and other factors that modulate expression of SLC7A11, GPX4, and ferroptosis-associated genes.(1,4,9,10)

Hypoxia, Mitochondrial Dysfunction, and Inflammation

Age-related changes in the choriocapillaris and Bruch’s membrane can compromise oxygen and nutrient delivery to the outer retina, leading to chronic hypoxia and mitochondrial stress in RPE cells.(9,13) Experimental hypoxia aggravates ferroptosis in RPE by enhancing Fenton chemistry and upregulating iron transport pathways, resulting in greater lipid peroxidation and cell death.(13) Mitochondrial dysfunction, a characteristic feature of AMD, further increases ROS production and susceptibility to ferroptosis.(14)

Ferroptosis also interacts with inflammatory pathways. Lipid peroxidation products such as 4‑hydroxynonenal can activate inflammasomes, while iron-induced ROS promote release of pro-inflammatory cytokines, creating a feed-forward loop of oxidative damage and inflammation in the retina.(1,4,9)

Ferroptosis in Major Retinal Diseases

Age-Related Macular Degeneration and Geographic Atrophy

Multiple lines of evidence implicate ferroptosis in the pathogenesis of dry AMD and geographic atrophy. Donor eyes with AMD show increased iron deposition in RPE, photoreceptors, and Bruch’s membrane, along with elevated oxidative damage markers consistent with iron-mediated lipid peroxidation.(8,15) Experimental models using oxidative stress or sodium iodate to damage RPE cells demonstrate ferroptotic features that can be mitigated by ferroptosis inhibitors or iron chelators.(6,11,16)

A recent review of mitochondria–lipid crosstalk in dry AMD proposes that mitochondrial dysfunction, altered lipid metabolism, and ferroptosis form an integrated pathogenic triad that accelerates RPE and photoreceptor degeneration.(14) Additional work describes ferroptosis as an “energetic villain” in AMD, linking age-related iron accumulation, impaired GPX4 activity, and chronic oxidative stress to lesion expansion in geographic atrophy.(5,17,18)

Retinal Ischemia–Reperfusion Injury

Retinal ischemia–reperfusion injury, as occurs in acute glaucoma, retinal vascular occlusion, or systemic hypotension, leads to rapid ROS generation and neuronal death. In rodent models, ischemia–reperfusion triggers iron accumulation, lipid peroxidation, and ferroptosis markers in retinal ganglion cells and inner retinal layers.(6,10,12) Treatment with ferrostatin‑1, liproxstatin‑1, or deferoxamine reduces neuronal loss and preserves retinal function, indicating that ferroptosis is a major contributor to ischemic retinal injury.(6,10,12)

Diabetic Retinopathy

Hyperglycaemia and chronic oxidative stress in diabetic retinopathy can promote ferroptosis through increased labile iron, advanced glycation end products, and impaired antioxidant defences.(4,7,19) Experimental diabetic models show upregulation of ferroptosis-related genes, accumulation of lipid peroxides, and retinal cell death that can be attenuated by ferroptosis inhibitors.(4,7,19) Although human data remain limited, these findings suggest that ferroptosis may intersect with apoptosis, pyroptosis, and other death pathways in diabetic retinal neurodegeneration.

Glaucoma and Retinal Ganglion Cell Death

Glaucoma involves progressive loss of retinal ganglion cells and their axons. Increased iron levels and lipid peroxidation have been observed in experimental glaucoma models, and ferroptosis inhibitors partially protect retinal ganglion cells from pressure-induced damage.(4,6,7) Nrf2 activation, iron chelation, and GPX4 upregulation have been proposed as potential approaches to reduce ferroptosis-mediated ganglion cell loss.(4,7)

Retinoblastoma and Inherited Retinal Disorders

In retinoblastoma, ferroptosis has been investigated both as a pathogenic mechanism and as a therapeutic tool. Autophagy-dependent ferritin degradation (ferritinophagy) can promote ferroptosis in drug-tolerant retinoblastoma cells, and pharmacologic induction of ferroptosis may help eradicate resistant tumour populations.(1,4,20) Evidence for ferroptosis in inherited retinal degenerations such as retinitis pigmentosa is emerging; experimental models suggest that ferroptotic mechanisms contribute to photoreceptor degeneration alongside apoptosis and necroptosis.(4,7,21)

Clinical Research and Therapeutic Landscape

Iron Chelation Strategies

Iron chelators such as deferoxamine and deferiprone are established treatments for systemic iron overload and have shown efficacy in mitigating ferroptosis in retinal models.(6,8,10–12) In retinal ischemia–reperfusion and light-induced damage, iron chelation reduces lipid peroxidation and preserves retinal structure and function.(6,10,12) However, systemic chelation carries risks including cytopenias and renal toxicity, and high-dose deferoxamine can itself cause retinal dysfunction, underscoring the need for careful dosing and monitoring.(8,15)

Localized ocular delivery of iron chelators is being explored preclinically, but clinical trials explicitly targeting retinal ferroptosis via chelation are limited. Ultimately, successful translation will require formulations that optimise retinal exposure while minimising systemic and ocular toxicity.(14,18)

Small-Molecule Ferroptosis Inhibitors

Ferroptosis-specific inhibitors such as ferrostatin‑1 and liproxstatin‑1 act as radical-trapping antioxidants that intercept lipid peroxyl radicals.(2,3) These agents robustly protect RPE and retinal neurons in vitro and in animal models, but their pharmacokinetics and safety profiles for human use remain under investigation.(1,4,10) Next-generation analogues with improved stability and reduced off-target effects are in development, and intravitreal or sustained-release delivery systems may be considered for chronic retinal diseases.

Combination strategies that pair ferroptosis inhibitors with anti-inflammatory or anti-apoptotic agents may provide synergistic neuroprotection in conditions where multiple cell death pathways are activated simultaneously.(1,4,6)

Upregulating GPX4 and Antioxidant Pathways

Augmenting the GSH–GPX4 axis is another therapeutic avenue. Nrf2 activators, cysteine donors (for example N‑acetylcysteine), and modulators of system Xc− can increase cellular antioxidant capacity and reduce susceptibility to ferroptosis.(9,10,19) In retinal models, Nrf2 activation protects against RPE and photoreceptor damage, partly by boosting glutathione synthesis and antioxidant enzyme expression.(9,14)

Direct enhancement of GPX4 expression or activity is technically challenging because GPX4 is an essential selenoprotein with tight regulatory control.(2,3,10) Gene therapy approaches aimed at increasing GPX4 or related antioxidant proteins in specific retinal cell populations are under early experimental investigation.(4,14,18)

Targeting Mitochondria–Lipid Crosstalk

Given the intertwined roles of mitochondrial ROS production, lipid metabolism, and ferroptosis, therapies aimed at stabilising mitochondrial function and modulating lipid composition are of interest.(14,18) Mitochondria-targeted antioxidants, optimized dietary PUFA–antioxidant balance, and modulators of lipid-remodelling enzymes may reduce ferroptotic risk in the ageing retina.(14,18) These strategies could complement direct ferroptosis inhibitors and address upstream drivers of oxidative stress.

Emerging Research Directions

Biomarkers of Ferroptosis in Vivo

Robust biomarkers are needed to monitor ferroptosis activity in patients and evaluate therapeutic interventions. Candidate markers include lipid peroxidation products such as 4‑hydroxynonenal and malondialdehyde, oxidized PE species, and iron-sensitive MRI or optical imaging techniques.(1,4,8,14) Circulating or intraocular levels of ferroptosis-related proteins (for example ACSL4, GPX4, SLC7A11, FSP1) may also provide insight but require validation in clinical cohorts.(1,4,10)

Integration with Retinal Imaging

Advanced imaging modalities—fundus autofluorescence, spectral-domain and swept-source optical coherence tomography (OCT), and OCT angiography—offer detailed structural information that can be correlated with underlying ferroptotic processes, particularly in AMD and ischemic conditions.(5,8,14) Linking imaging biomarkers with biochemical indicators of ferroptosis may help determine when and where ferroptosis is most active, guiding timing and selection of interventions.

Combination Therapies and Stage-Specific Targeting

Because retinal diseases typically involve multiple overlapping death pathways, combined modulation of ferroptosis, apoptosis, pyroptosis, and inflammatory processes is likely necessary for optimal neuroprotection.(1,4,6,7) Disease stage may also influence the relative contribution of ferroptosis. For example, early AMD may be dominated by iron accumulation and oxidative stress, whereas advanced geographic atrophy includes complement-mediated damage and other mechanisms.(5,8,14,17,18) Stage-specific targeting strategies that adjust the intensity and focus of ferroptosis inhibition over time are an important direction for future research.

Safety and Physiological Roles of Ferroptosis

Iron is essential for normal retinal function, including phototransduction and mitochondrial energy metabolism.(8,15) Chronic or excessive ferroptosis inhibition could theoretically impair necessary iron-dependent processes or alter host defence mechanisms.(1,4,8) Long-term safety studies will therefore be crucial as ferroptosis-targeted therapies move toward clinical use.

Conclusion

Ferroptosis has emerged as a central mechanism of retinal cell death driven by iron-dependent lipid peroxidation and failure of antioxidant defences. The unique metabolic and structural features of the retina—high PUFA content, intense oxidative load, and complex iron handling—make it particularly prone to ferroptotic injury. Experimental and pathological evidence implicates ferroptosis in the pathogenesis of AMD, retinal ischemia–reperfusion injury, diabetic retinopathy, glaucoma, and retinoblastoma, among other ocular diseases.(1,4–8,10–12,14–21)

Modulation of iron homeostasis, reinforcement of the GSH–GPX4 axis, activation of alternative antioxidant systems, and direct inhibition of lipid peroxidation all show promise in preclinical models. Translating these approaches into clinically effective therapies will require robust biomarkers of retinal ferroptosis, precise targeting to vulnerable cell types, and thorough evaluation of long-term safety. As understanding of ferroptosis crosstalk with mitochondrial dysfunction, inflammation, and other cell death pathways deepens, ferroptosis-targeted strategies may become an important component of comprehensive neuroprotective therapy for retinal disease.

This article is for educational purposes only and reflects current scientific literature at the time of writing.

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