Electroacupuncture Attenuates Cerebral Ischemia–Reperfusion Injury by Inhibiting Ferroptosis via the p53/SLC7A11 Pathway

Abstract

Acupuncture has demonstrated efficacy in treating post-stroke complications. Electroacupuncture (EA) ameliorates neurological outcomes in cerebral ischemia models, yet its mechanisms remain unclear. This study investigated EA's role in reducing cerebral ischemia–reperfusion injury (CIRI) in a rat model, focusing on ferroptosis. A CIRI model was established via the MCAO/R method. Rats were randomly assigned to five experimental groups: Sham, MCAO/R, MCAO/R + COTI-2, MCAO/R + EA and MCAO/R + COTI-2 + EA. We evaluated neurological function with Zausinger scoring. 2,3,5-Triphenyltetrazolium chloride (TTC) staining assessed infarct size, while haematoxylin–eosin (HE) staining examined neuronal damage. Transmission electron microscopy analysed mitochondrial changes associated with ferroptosis, and Perl staining measured iron levels in neurons. The biomarkers associated with ferroptosis, including glutathione (GSH), reactive oxygen species (ROS) and malondialdehyde (MDA), were measured. The expression of p53, SLC7A11 and GPX4 was assessed by qRT-PCR and Western blot. EA enhanced neurological function, reduced the infarct size, alleviated excessive serum iron accumulation, increased antioxidant markers (GSH, GPX4) and decreased lipid peroxidation levels (ROS, MDA), attenuating lipid peroxidation. Additionally, it reversed mitochondrial morphological changes associated with ferroptosis. qRT-PCR and Western blot analyses revealed that EA downregulated p53 expression while upregulating SLC7A11 and GPX4 expression. In summary, ferroptosis was activated after CIRI, and EA ameliorated neurological deficits in cerebral ischemia models by modulating the p53/SLC7A11 axis to counteract oxidative stress-induced ferroptosis, ultimately providing neuroprotective benefits.