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

Abstract

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.