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 vision loss in older adults due to optic nerve damage. Despite efforts to treat the associated vascular issues or oxidative stress, the permanent loss of retinal ganglion cells (RGCs) remains unpreventable, revealing a gap in understanding the progression from injury to irreversible axonal failure.

Researchers have now discovered that lipid peroxidation, a type of cellular damage, plays a crucial role in this neurodegeneration. Using both human NAION retinas and a reliable mouse model, they observed significant phospholipid peroxidation occurring in the retina after ischemic injury. By specifically increasing the production of glutathione peroxidase 4 (GPX4) in RGCs, the enzyme capable of neutralizing phospholipid hydroperoxides, they found remarkable protection for RGCs and their axons, as well as restored visual function.

Furthermore, mitochondrial-targeted GPX4 proved even more effective, pointing to mitochondria as a vulnerable area in NAION. Through in vivo imaging, they confirmed that GPX4 overexpression restored axonal and retinal mitochondrial levels, improved ATP energy production, and reduced oxidative stress in injured optic nerves. In addition, GMX4 expression enhanced axonal transport and retinal projections to key visual areas, stabilizing the connections in the visual pathway.

The findings were further validated by using Ebselen, a GPX4 mimic, demonstrating that lipid peroxide detoxification is a promising, validated therapeutic approach for NAION. Overall, this research establishes that ischemia-induced lipid peroxidation is a critical factor in NAION-induced neurodegeneration and identifies GPX4 as a key factor in protecting RGCs from permanent damage.