Aerobic exercise regulates the cGAS/STING signaling pathway and inhibits ferroptosis to alleviate ischemic stroke.

Aerobic exercise at the appropriate intensity alleviates motor dysfunction after ischemic stroke (IS); however, its regulatory mechanisms remain to be elucidated. In this study, the neuroprotective effects of exercise and the related mechanisms were investigated using a rat middle cerebral artery occlusion (MCAO) model and an HT22/PC12 cell oxygen-glucose deprivation/reperfusion (OGD/R) model. The rats were subjected to daily exercise training for durations of 3, 7 or 14 days post-surgery. The results revealed that exercise, particularly the 14-day regimen, significantly reduced the mNSS and infarct area, restored the number of Nissl bodies, and ameliorated cortical pathology. Exercise also decreased Fe²+, MDA, and IREB2 levels and increased SOD, GPX4, and SLC7A11 levels, indicating the inhibition of ferroptosis. In addition, the ferroptosis inhibitor Fer-1 attenuated OGD/R-induced damage in HT22 and PC12 cells. In terms of molecular mechanisms, we revealed that the cGAS/STING signaling pathway was activated and that knockdown of cGAS or STING restored cell viability and mitochondrial structure by inhibiting ferroptosis and reducing cell damage. Importantly, exercise also alleviated IS progression in rats by downregulating the expression of cGAS and STING. In conclusion, aerobic exercise inhibits ferroptosis via suppression of the cGAS/STING pathway, thereby alleviating IS progression.