Dexmedetomidine Inhibits Ferroptosis by Regulating the SRY-Box Transcription Factor 9/Divalent Metal Transporter-1 Axis to Alleviate Cerebral Ischemia/Reperfusion Injury

Abstract

Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with ferroptosis. Dexmedetomidine (Dex) exerts neuroprotective activity after cerebral IRI. Our work focused on probing the pharmacologic effect of Dex on ferroptosis during cerebral IRI and the mechanisms involved. Cerebral IRI models were established by oxygen–glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium chloride (TTC) staining was utilized to detect cerebral infarct size and mNSS was performed to evaluate neurologic deficits. Brain pathologic changes were analyzed by HE staining. Lipid peroxidation level was detected by C11-BODIPY staining, and Fe²⁺ and MDA levels were measured using the kits. Cell vitality was examined by CCK-8 assay. Dual-luciferase reporter and ChIP assays were adopted to determine the interaction between SOX9 and DMT1 promoter. Dex ameliorated ferroptosis and neuronal death induced by MCAO and OGD/R. SOX9 upregulation abolished the inhibitory effect of Dex on OGD/R-induced ferroptosis and neuronal death in SH-SY5Y cells. Our further trials showed that SOX9 transcriptionally activated DMT1 expression. As expected, DMT1 overexpression prevented Dex-induced decrease in ferroptosis and neuronal death in OGD/R-treated SH-SY5Y cells. Dex inhibited ferroptosis to exert neuroprotection effects on cerebral IRI by inactivating the SOX9/DMT1 axis.