Hydrogen Sulfide: A Potential Therapeutic Treatment to Mitigate Pressure-induced Ferroptosis in Retinal Ganglion Cells

Glaucoma can lead to retinal ganglion cells (RGCs) death and permanent vision impairment. Elevated intraocular pressure (IOP) is the main cause of glaucomatous damage. However, only controlling IOP does not completely restrain RGCs loss in glaucoma, and the inner workings remain elusive. In this study, we found that iron metabolism disorders, impaired mitochondrial function, and ferroptosis participated in the pressure elevation by analysing the retinas of mice with chronic pressure elevation. Thus, these pathways may be involved in RGCs injury by elevated IOP. In vitro studies confirmed that chronic pressure elevation promoted iron import, inhibited iron export, and triggered the unusual deposition of ferrous iron (Fe2+). At the same time, mitochondrial deficiency also caused an abnormal buildup ferrous iron and the loss of RGCs. In addition, chronic stress elevation and mitochondrial defects caused enhanced reactive oxygen species (ROS) levels and diminished glutathione (GSH) levels, and chronic stress elevation also caused glutathione peroxidase 4 (GPx4) exhaustion. By exploring NADPH oxidase 2 (NOX2) knockout mice, it was found that NOX2 was one of the more effective inducers of chronic pressure elevation induced GPx4 reduction compared to iron metabolism disorders, which further induced ferroptosis in RGCs. In conclusion, the present study revealed that chronic pressure elevation caused ferroptosis in RGCs by disrupting iron metabolism and damaging mitochondrial function. Furthermore, we demonstrated that hydrogen sulfide (H2S) played an iron chelating and antioxidant role in the protection of RGCs, which provides a research direction for the understanding and treatment glaucoma.