SIRT7 inhibits cerebral ischemic injury by inhibiting microglia M1 polarization via desuccinylation of NAMPT.

Abstract

Cerebral ischemic injury continues to be a leading cause of mortality and disability worldwide. Although Sirtuin 7 (SIRT7), a desuccinylase, is known to regulate protein expression, its role in cerebral ischemia remains unclear. This study utilized a middle cerebral artery occlusion (MCAO) mouse model and an oxygen-glucose deprivation (OGD)-induced microglial model to elucidate the mechanisms of SIRT7. Microglial M1/M2 polarization was assessed via qPCR and immunofluorescence, while underlying mechanisms were analyzed using western blot and co-immunoprecipitation. Our results demonstrated that SIRT7 was significantly downregulated following cerebral ischemic injury. SIRT7 overexpression inhibited OGD-induced M1 polarization, whereas promoting M2 polarization. Mechanistically, SIRT7 mediated nicotinamide phosphoribosyltransferase (NAMPT) desuccinylation and subsequent proteasomal degradation, thereby suppressing M1 polarization and ultimately attenuating brain injury progression. These findings offer novel insights into the regulatory role of SIRT7 in inflammatory responses and suggest that targeting the SIRT7-NAMPT axis could serve as a promising therapeutic strategy for cerebral ischemia-related disorders.