Cottonseed oil alleviates ischemic stroke injury by inhibiting ferroptosis

Abstract Ferroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to Blood-Brain Barrier (BBB) disruption followed by secondary iron-loaded transferrin (TF) influx. Ferroptosis was only recently identified as a novel and independent cell death pathway, characterized by iron dependent lipid peroxidation, decline of GSH, GPX4 and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats. The results showed subcutaneous injection of 1.3 mL/kg CSO every other day for three weeks could significantly ameliorate middle cerebral artery occlusion-reperfusion (MCAO-R) induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries, protected BBB integrity and reduced influx of iron ion and TF; up-regulated anti-ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down-regulated ferroptosis related protein ACSL4, increased the activity of GSH, SOD, and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment. In conclusion, we report that CSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.