GPX4 promotes optic nerve regeneration and retinal ganglion cell neuroprotection.

Glaucoma is an optic neuropathy characterized as progressive degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve (ON). Recently, lipid peroxidation and ferroptosis have been linked to experimental glaucoma, suggesting a new therapeutic strategy. Here, we report that glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation, is upregulated in surviving and regenerating RGCs in two mouse optic neuropathy models, traumatic ON crush and glaucoma. To explore the potential neuroprotective role of GPX4, we test adeno-associated virus-mediated RGC-specific overexpression of GPX4 in these models and found that GPX4 promotes significant ON regeneration, RGC survival, and visual functional preservation. Interestingly, lipid peroxidation inhibitor liproxstatin-1, but not ferroptosis inhibitor deferiprone, presents significant RGC neuroprotection and axon regeneration, indicating the detrimental role of lipid peroxidation but not ferroptosis in optic neuropathies, and the therapeutic potential of modulating lipid peroxidation through GPX4.