Photobiomodulation for Photoreceptor Rescue in Retinal Disease: Mitochondrial, Redox, Vascular, and Translational Perspectives—A Narrative Review

RGC-specific reversal of lipid peroxidation drives neuroprotection and vision restoration in optic nerve ischemia by targeting GPX4

Nonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of acute optic nerve-related vision loss in older adults, yet no disease-modifying therapy exists. Although ischemia is a defining feature of NAION, prior therapeutic efforts targeting vascular insufficiency or nonspecific oxidative stress have failed to prevent irreversible retinal ganglion cell (RGC) degeneration, underscoring an unresolved mechanistic gap between ischemic insult and permanent axonal failure. In this endeavour, we identify lipid peroxidation as an important driver of neurodegeneration in NAION. Analyses of human NAION retina, together with a rigorously validated mouse model, demonstrated a remarkable activation of phospholipid peroxidation within the retina following ischemic injury. RGC-specific overexpression of glutathione peroxidase 4 (GPX4), the only known enzyme capable of directly detoxifying phospholipid hydroperoxides within biological membranes, confers striking protection of RGC survival, axonal integrity, and visual function. We further demonstrate that mitochondrial-targeted GPX4 provides superior protection, suggesting mitochondria as a critical locus of lipid peroxidation–driven vulnerability in NAION. Leveraging real-time multiparametric in vivo imaging to directly interrogate axonal metabolism and function, we demonstrate that RGC-specific GPX4 overexpression robustly restores axonal and retinal mitochondrial abundance, improves ATP bioenergetics, and suppresses superoxide stress following optic nerve ischemia. Mitochondria-targeted GPX4 expression further restores axonal transport and retinofugal projections to central visual targets, thereby stabilizing visual pathway connectivity. Notably, these neuroprotective effects are recapitulated by Ebselen, a clinically tested GPX mimetic, identifying lipid peroxide detoxification as a translatable and imaging-validated therapeutic strategy. Collectively, this work establishes ischemia-induced lipid peroxidation as an essential driver of neurodegeneration in NAION and identifies GPX4 as a key molecular determinant of retinal ganglion cell resilience. One Sentence Summary Lipid peroxidation as mechanism of vision loss in NAION, and targeting GPX4 leads to neuroprotection and visual restoration

Quercetin is associated with photoreceptor protection in retinal degeneration.

Retinal degeneration (RD) is a group of retinopathies characterized by progressive photoreceptor death and chronic neuroinflammation. Quercetin (QUE) is a natural flavonol with potent anti-inflammatory and free-radical scavenging properties. However, its protective effects against RD remain poorly characterized. This study aims to investigate the therapeutic potential of QUE on RD.In vitro and in vivo models of sodium iodate (NaIO3)-induced oxidative damage were used to evaluate the effects of QUE in RD. NaIO3 was used to induce oxidative damage in 661W cells. QUE was added to the cell cultures, and cell viability and oxidative markers were assessed. In vivo, QUE was delivered into the vitreous cavity of NaIO3-induced RD mice, followed by morphological analysis, visual function evaluation, behavioral testing, and Western blot detection.QUE protected 661W cells from NaIO3-induced oxidative damage by reducing intracellular reactive oxygen species, restoring mitochondrial membrane potential, and alleviating mitochondrial membrane pore disruption. In vivo, intravitreal QUE injection preserved retinal structure, reduced lesion area, elevated electroretinogram P-wave amplitude, and improved behavioral performance. QUE administration was accompanied by alleviated oxidative stress, inhibited glial activation, reduced pro-inflammatory cytokines, and elevated p-PI3K and p-AKT expression in RD. Neuroinflammation and oxidative stress are involved in RD pathology. These findings provide preliminary evidence that QUE exerts protective effects on photoreceptors in NaIO₃-induced RD. No causal relationship between PI3K/AKT activation and the retinal protection of QUE was established in this study.

Lactate Signaling and Lactylation in Retina: From Physiological Warburg Effect to Pathological Metabolic Reprogramming.

Lactate was once regarded merely as a byproduct of glycolysis, but is now recognized as a multifunctional metabolite that coordinates energy redistribution, intercellular communication, receptor-mediated signaling, and epigenetic regulation. In the retina, these functions are especially consequential because visual processing depends on a highly specialized and energetically demanding tissue, characterized by steep oxygen gradients, a dual vascular supply, and tightly integrated metabolic crosstalk among photoreceptors (PCs), Müller glia, the retinal pigment epithelium, vascular cells, and retinal ganglion cells. In this review, we synthesize current advances in lactate signaling and lactylation in the retina, and examine how their dysregulation contributes to neovascularization, inflammation, and neurodegeneration in disorders including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis and glaucoma. Drawing from these metabolic insights, therapeutic interventions targeting lactate signaling and lactylation are discussed as potential approaches to mitigate retinal abnormalities. Collectively, this review highlights the central importance of lactate signaling and lactylation in retinal physiology and pathology, and provides a conceptual framework for developing metabolic interventions aimed at restoring retinal lactate homeostasis.

Dual Targeting of Galanin Receptor 3 Signaling and Redox Homeostasis Enhances Photoreceptor Survival in Retinas of rd10 Mice

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerative disorders characterized by progressive photoreceptor loss and vision impairment, for which broadly applicable mutation-independent therapies remain limited. To examine the therapeutic potential of combined galanin receptor 3 (GALR3) inhibition and antioxidant therapy in a mutation-independent context, we utilized the rd10 mouse model of RP. We first evaluated the effects of individual treatments with the GALR3 antagonist SNAP-37889 and the antioxidant quercetin, followed by a combined treatment regimen to determine whether simultaneous targeting of neuroinflammatory and oxidative stress pathways provides enhanced retinal protection. Treatment efficacy was assessed using functional and morphological analyses, including electroretinography (ERG) to measure retinal function, optical coherence tomography (OCT) to evaluate retinal structure in vivo, and histological and immunohistochemical analyses to quantify photoreceptor survival and markers of retinal oxidative stress and inflammation. Although the expression levels of individual inflammatory and oxidative stress markers did not consistently exhibit additive responses, the combined treatment produced greater photoreceptor survival and preservation of photopic retinal function than either monotherapy alone. These findings support the hypothesis that simultaneous modulation of oxidative stress and neuroinflammation provides greater neuroprotective benefits, establish a foundation for the development of mutation-independent therapeutic strategies for RP, and identify GALR3 as a promising therapeutic target.

Chronic Hypoxic Signalling Reprograms Metabolism and Alters Redox and Lipid Homeostasis in Rod Photoreceptors

Targeting ferroptosis in ocular diseases: mechanisms, clinical implications, and therapeutic horizons.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly implicated in selected ocular diseases, although its causal relevance varies across disease entities. The retina and retinal pigment epithelium are biologically susceptible to ferroptosis-related injury because of their high oxygen demand, abundant polyunsaturated lipids, mitochondrial activity, light exposure, and tightly regulated iron handling. This review summarizes core mechanisms of ocular ferroptosis, including iron uptake and export, glutathione-glutathione peroxidase 4 (GPX4)-dependent antioxidant defense, lipid peroxidation, mitochondrial dysfunction, neuroinflammation, and blood-retina barrier disruption. We discuss evidence from major degenerative, vascular, ischemic, hereditary, infectious, and immune-mediated retinal diseases, with particular attention to glaucoma, age-related macular degeneration, diabetic retinopathy, ocular toxoplasmosis, uveitis, retinal vasculitis, and inflammatory chorioretinopathy. We also evaluate ferroptosis-targeted therapeutic strategies, proposed operational criteria for defining ferroptosis in retinal disease, and candidate structural, functional, biochemical, and imaging endpoints for future translational studies. Current evidence supports ferroptosis as a context-dependent contributor to retinal injury rather than a uniform pathogenic mechanism. Future studies should integrate cell-type-resolved biomarkers, lipidomic and imaging readouts, functional rescue experiments, and clinically meaningful visual outcomes to clarify when ferroptosis modulation may support vision preservation.