Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.

Retinal ischemia (RI) is a prominent pathological feature of several ocular diseases, including diabetic retinopathy, glaucoma, and retinopathy of prematurity. These diseases are major causes of adult and childhood blindness worldwide. Retinal and optic nerve degeneration also involves non-ischemic mechanisms. Severe or sustained RI can cause irreversible retinal injury and visual impairment. RI can trigger oxidative stress, inflammatory responses, and mitochondrial dysfunction, which can contribute to cell death. Ferroptosis is a distinct form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxides in membrane phospholipids. Accumulating preclinical evidence indicates that ferroptosis-associated processes may contribute to retinal and optic nerve injury. Targeting ferroptosis-related pathways may offer promising approaches to mitigate cellular damage in these diseases. In this review, we summarize the ferroptosis mechanisms relevant to retinal and optic nerve injury and evaluate evidence from experimental models, cell types, pharmacological rescue studies, and genetic approaches. By comparing experimental models, cell types, and mechanistic evidence, we distinguish direct neuronal findings from non-neuronal ocular responses and assess whether the results support ferroptosis or broader oxidative stress. We also identify the evidence needed to assess the translational relevance of ferroptosis-targeted strategies in retinal and optic nerve diseases.

Background: Retinopathy of prematurity (ROP) is a predominant contributor to preventable childhood blindness driven by oxidative stress and inflammation, but with limited treatment options. Safe, non-invasive adjunctive strategies become attractive. Lutein displays antioxidant and anti-inflammatory properties, but its clinical efficacy remains controversial. We proposed that formulating lutein in extra-virgin olive oil (EVOO) might enhance its absorption and efficacy in ROP. Here, we evaluated the effects of lutein-in-EVOO (LEVOO) in oxygen-induced retinopathy (OIR), a mouse model of ROP. Methods: C57BL/6J mouse neonates received daily gavage of LEVOO (0.4 μg/g, 1.8 μg/g and 3.6 μg/g of lutein in EVOO) after OIR challenge from postnatal day (P) 12 to P16. Assessments were conducted at P17, including retinal vasculature, function, cytoarchitecture, inflammation, and oxidative damage; serum biochemical and antioxidant profiles; and proteomic analysis and targeted retinal metabolomic analysis. Results: Oral supplementation of LEVOO was well-tolerated and safe in mouse neonates. It reduced retinal avascular and neovascular areas, increased electroretinographic b-wave amplitudes, and restored amacrine cells and rod bipolar cells. LEVOO administration reduced oxidative damage and activated microglia. LEVOO administration inhibited the hypoxia-inducible factor-1α (HIF-1α)/macrophage migration inhibitory factor (MIF) signaling and low-density lipoprotein receptor-related protein-1 (LRP1)-dependent cyclophilin A (CypA)/matrix metalloproteinase-9 (MMP9) signaling. It also helped to partially restore retinal docosahexaenoic acid and dopamine in OIR mice. Conclusions: LEVOO demonstrated multifaceted efficacy in OIR. It reconstructed retinal vasculature, restored retinal function, and rescued neuronal cell loss with strong antioxidative and anti-inflammatory effects. Collectively, these findings establish LEVOO as a promising non-invasive complementary strategy for ROP.