OAC1 improves mitofusin 2 expression to alleviate neuronal injury following experimental ischemic stroke.

Recent research indicates that mitofusin 2 (MFN2) plays a pivotal role in the neuroprotective effects achieved by silencing nuclear receptor subfamily 6 group A member 1 (NR6A1) during cerebral ischemia. While NR6A1 is known to inhibit octamer-binding transcription factor 4 (OCT4), the regulatory relationship between OCT4 and MFN2 remains unknown. This study explores the neuroprotective effects of OCT4-activating compound 1 (OAC1), an OCT4 activator, against cerebral ischemia/reperfusion injuries and its underlying mechanism. In a murine stroke model, administration of OAC1 (3 mg/kg) significantly reduced brain infarction of mice and loss of MFN2. Notably, OAC1 treatment mitigated neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in a dose-dependent manner. Additionally, OAC1 treatment also alleviated dysfunction of mitochondria and endoplasmic reticulum stress. Moreover, OAC1 application preserved both OCT4 and MFN2 expression following OGD/R, and MFN2 facilitate protective function of OAC1 against neuronal damage induced by OGD/R. Our results demonstrate that OAC1 can alleviate neuronal damage in cerebral ischemia by activating the OCT4/MFN2. These findings offer novel insights into MFN2 regulation and highlight OCT4's potential as a therapeutic target for cerebral ischemia.