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Yinaoxin granule alleviates cerebral ischemia-reperfusion injury by ferroptosis inhibition through Nrf2 pathway activation

Jingyu Weng,Lang Liu,Shuming Li,Yuangui Yang,Rui Zhou,Zhen Zhang,Yanru Liu,Lin Chen,Zeyu Feng,Zhishu Tang,Hongbo Xu

Background Lipid peroxide accumulation plays significant roles in cerebral ischemia-reperfusion injury (CIRI) through various mechanisms, including ferroptosis. Preserving the neuronal metabolic equilibrium and averting cell death during cerebral Ischemia-reperfusion are pivotal for protecting brain function. Yinaoxin granule (YNX) is a widely used Chinese herbal preparations for treating cerebrovascular diseases, but pharmacological mechanism remains ambiguous.. Purpose The aim in this study was to assess the effectiveness of YNX in treating CIRI and to investigate the underlying mechanisms. Methods The active ingredients of YNX were quantified using high-performance liquid chromatography. To explore the effects of YNX on CIRI and ferroptosis, both an in vitro oxygen-glucose deprivation and reperfusion model and a middle cerebral artery occlusion and reperfusion rat model were used. To assess the neuroprotective effects of YNX in the latter, neurological scores and cerebral blood flow were evaluated. Neuronal damage was determined through 2,3,5-triphenyltetrazolium chloride, Nissl, and H&E staining. Ferroptosis-related markers, including ferrous ion, glutathione, 4-hydroxynonenal, and malondialdehyde were also investigated. Furthermore, the gene expression and protein levels of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and glutamate-cysteine ligase modulator (GCLM) were determined. Results YNX enhanced neurological scores and cerebral blood flow, reduced infarct volume, and rescued necrotic neurons in rats. Additionally, YNX mitigated lipid peroxidation and upregulated the SLC7A11, GCLM, and GPX4 levels. The absence of Nrf2 rendered neurons more susceptible to ischemia-reperfusion damage and abrogated the anti-ferroptotic neuroprotective effects of YNX. Conclusion YNX activates the Nrf2 pathway, resulting in the transcription of genes associated with antioxidants, including SLC7A11, GCLM, and GPX4. This suggests that YNX reduces lipid peroxidation and alleviates ferroptosis-induced CIRI.