Restoration of mitophagy by crebanine suppresses sevoflurane-induced microglial activation and cognitive deficits by blocking mitochondrial DNA-triggered cGAS–STING pathway

Sevoflurane, a volatile anesthetic in widespread clinical use, is increasingly implicated in the pathogenesis of postoperative cognitive dysfunction. Although neuroinflammation driven by microglial activation is a recognized contributor, the upstream mechanisms linking anesthesia to this inflammatory response remain poorly defined. Crebanine, a natural isoquinoline alkaloid with well-known anti-inflammatory properties, remains unexplored for its impact on mitochondrial quality control during anesthetic neurotoxicity. Herein, we investigated whether crebanine protects against sevoflurane-induced cognitive deficits by restoring microglial mitophagy and suppressing the mitochondrial DNA (mtDNA)-cGAS-STING pathway. In BV2 microglial cells, we found that sevoflurane exposure disrupted mitophagic flux, leading to mitochondrial dysfunction, excessive mitochondrial ROS generation, and subsequent leakage of mtDNA into the cytosol. This cytosolic mtDNA triggered the cGAS-STING pathway, driving pro-inflammatory cytokine production and promoting M1-like polarization. Crebanine treatment potently restored mitophagic flux, curtailed mtDNA release, and deactivated the inflammatory cascade, shifting microglia toward an anti-inflammatory M2-like phenotype. Pharmacological inhibition of mitophagy with 3-MA or direct activation of STING using DMXAA completely abolished the protective effects of crebanine, confirming its neuroprotection depends on this specific pathway. In animal experiments, administration of crebanine to aged male Sprague-Dawley rats markedly attenuated sevoflurane-induced hippocampal neuroinflammation and neuronal apoptosis, ultimately preserving spatial learning and memory function, as assessed by the Morris water maze test. Collectively, our findings delineate a mechanism wherein crebanine exerts its neuroprotective effects by restoring microglial mitophagy, thereby suppressing mtDNA-mediated cGAS-STING signaling and preserving cognitive function. This positions the mitophagy-mtDNA-cGAS-STING axis as a viable therapeutic target for managing anesthesia-induced neurocognitive decline.