Treadmill Training Reduces Cerebral Ischemia-Reperfusion Injury by Inhibiting Ferroptosis through Activation of SLC7A11/GPX4

The mechanism by which exercise training attenuates cerebral ischemia/reperfusion (I/R) injury, especially in the regulation of iron level in neuronal damage, has not been systematically studied. Here, we showed that treadmill training inhibited ferroptosis after I/R injury in rats. Modified neurologic severity score (mNSS) test showed that the motor function, reflex, and balance abilities in the I/R injury rats after treadmill intervention were significantly improved. Treadmill training decreased the level of lipid peroxides in the cerebral cortex of ischemic rats. We found that the protein levels of ferroptosis-related proteins including nuclear transcription factor E2-related factor 2 (Nrf2), cystine/glutamate reverse transporter (SLC7A11), and glutathione peroxidase 4 (GPx4) were decreased in rats after cerebral I/R injury, while treadmill training prevented the reduction of these proteins. Furthermore, we demonstrated that erastin- (a ferroptosis activator-) induced downregulation of SLC7A11 reversed the neuroprotective effect of treadmill training. This study provides the first evidence suggesting that treadmill training suppresses ferroptosis by activating the SLC7A11/GPx4 pathway, thereby protecting against cerebral I/R injury.