Protecting Neurons in Retinal and Optic Nerve Diseases: The Role of Ferroptosis-Associated Pathways

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.