Glycine Alleviates H₂O₂-Induced Ferroptosis in Mouse Hippocampal Neuron HT22 Cells via the GlyRɑ1/USP35/FPN1...

Ferroptosis is a novel form of programmed cell death driven by iron-dependent lipid peroxidation, which is present in many cerebrovascular diseases that include ischemic stroke. Glycine, one of the primary components of glutathione (GSH), plays an important role in anti-oxidation, against ischemic damage, immunity improvement, and so on. However, the molecular mechanism by which glycine alleviates ferroptosis is not yet clear, especially in neurons. In the current study, we demonstrated the cytoprotective role of glycine in H₂O₂ and Erastin-induced ferroptosis in vitro in the HT22 cells. It was shown that glycine significantly improved neuronal survival along with suppressed reactive oxygen species (ROS) and upregulated expression levels of GSH, ubiquitin-specific peptidase 35 (USP35), GPX4, ferroportin (FPN1), and FTH1. Mechanically, using a glycine receptor α1 (GlyRα1) inhibitor (sodium salicylate), we indicated that glycine regulates H₂O₂-induced neuronal injury through the GlyRα1/USP35/FPN1 signaling axis. In conclusion, the results of the present study implied that glycine exerts neuroprotective effects by modulating ferroptosis through the GlyRα1/USP35/FPN1 axis, thereby preventing cell death after oxidative stress injury.