PRMT5 promotes cerebral ischemia/reperfusion-induced ferroptosis via Nrf2/SLC7A11/GPX4 signaling

Numerous research findings have indicated that neuronal ferroptosis is a significant pathological alteration in cerebral ischemia/reperfusion (I/R) injury, and the inhibition of this process can markedly ameliorate I/R injury. Preliminary results from our research group demonstrated that the arginine methyltransferase 5 (PRMT5) protein can modulate the neuroinflammatory response and neuronal pyroptosis associated with cerebral I/R injury through the activation of the NF-κB/NLRP3 signaling pathway. In this study, we further investigate the PRMT5 role in neuronal ferroptosis regulation in cerebral I/R injury. In vitro findings demonstrated that PRMT5 knockdown led to an elevated glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio and relative superoxide dismutase (SOD) activity, a reduction in malondialdehyde (MDA) levels, and an upregulation of SLC7A11 and GPX4 expression, thereby reducing neuronal ferroptosis. Conversely, PRMT5 overexpression appeared to promote neuronal ferroptosis. In addition, in vivo studies that used the PRMT5-specific inhibitor, LLY-283, confirmed that PRMT5 inhibition attenuated neuronal ferroptosis in cerebral I/R injury. Finally, the present study demonstrated that PRMT5 regulated ferroptosis through the activation of the Nrf2/SLC7A11/GPX4 signaling pathway. In conclusion, PRMT5 may be a potential therapeutic target for cerebral I/R injury.