Progressive retinal ganglion cells (RGCs) death that triggered by
retinal ischemia reperfusion (IR), leads to irreversible
visual impairment and
blindness, but our knowledge of post-IR neuronal death and related mechanisms is limited. In this study, we first demonstrated that apart from necroptosis, which occurs before apoptosis, ferroptosis, which is characterized by
iron deposition and lipid peroxidation, is involved in the whole course of
retinal IR in mice. Correspondingly, all three types of RGCs death were found in retina samples from human
glaucoma donors. Further, inhibitors of apoptosis, necroptosis, and ferroptosis (z-VAD-FMK, Necrostatin-1, and Ferrostatin-1, respectively) all exhibited marked RGC protection against IR both in mice and primary cultured RGCs, with
Ferrostatin-1 conferring the best
therapeutic effect, suggesting ferroptosis plays a more prominent role in the process of RGC death. We also found that activated microglia, Müller cells, immune responses, and intracellular
reactive oxygen species accumulation following IR were significantly mitigated after each inhibitor treatment, albeit to varying degrees. Moreover,
Ferrostatin-1 in combination with
z-VAD-FMK and
Necrostatin-1 prevented IR-induced RGC death better than any inhibitor alone. These findings stand to advance our knowledge of the post-IR RGC death cascade and guide future
therapy for RGC protection.