AbstractBackground and aimRepetitive transcranial magnetic stimulation (rTMS) has been found to attenuate cerebral ischemia/reperfusion (I/R) injury. However, its effects and mechanism of action have not yet been clarified. It has been reported that cerebral I/R injury is closely associated not only with ferroptosis but also with inflammation. Hence, the current study aimed to investigate whether high‐frequency rTMS attenuates middle cerebral artery occlusion (MCAO)‐induced cerebral I/R injury and further to elucidate the mediatory role of ferroptosis and inflammation.MethodsThe protective effects of rTMS on experimental cerebral I/R injury were investigated using transient MCAO model rats. Neurological scores and pathological changes of cerebral ischemic cortex were assessed to evaluate the effects of rTMS on cerebral I/R injury. The involvement of ferroptosis and that of inflammation were examined to investigate the mechanism underlying the effects of rTMS.ResultsHigh‐frequency rTMS remarkably rescued the MCAO‐induced neurological deficits and morphological damage. rTMS treatment also increased the mRNA and protein expression of glutathione‐dependent peroxidase 4, decreased the mRNA and protein levels of acyl‐CoA synthetase long‐chain family member 4 and transferrin receptor in the cortex. Moreover, rTMS administration reduced the cerebrospinal fluid IL‐1β, IL‐6, and TNF‐α concentrations.ConclusionThese findings implicated that high‐frequency rTMS alleviates MCAO‐induced cerebral I/R injury, and the underlying mechanism could involve the inhibition of ferroptosis and inflammation. Our study identifies rTMS as a promising therapeutic agent for the treatment of cerebral I/R injury. Moreover, the mechanistic insights into ferroptosis and inflammation advance our understanding of it as a potential therapeutic target for diseases beyond cerebral ischemia stroke.