Berberine Ameliorates Neuroinflammation by cGAS-STING-NLRP3 Axis in Cerebral Ischemia/Reperfusion Injury

Aims: This study aimed to investigate the protective mechanisms of berberine (BBR), the primary bioactive alkaloid of Coptidis rhizoma, against cerebral ischemia/reperfusion injury (CIRI), focusing on its integrated modulation of neuroinflammation and oxidative stress. Methods: A combination of in vivo and in vitro models was utilized. Neuroprotection was assessed in a rat model of transient middle cerebral artery occlusion (MCAO). Cytoprotective effects were further verified in SH-SY5Y neuroblastoma cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Molecular targets were identified through integrated analysis of in vivo and in vitro datasets. Results: BBR administration conferred significant neuroprotection in MCAO rats, evidenced by reduced cerebral infarct volume, improved neurological scores, enhanced antioxidant capacity (elevated GSH and SOD), and preserved mitochondrial integrity. In OGD/R-injured SH-SY5Y cells, BBR similarly increased GSH and SOD activity while decreasing levels of oxidized dsDNA, ROS, IL-1β, and TNF-α. Mechanistically, these benefits were attributed to the suppression of the cGAS/STING/NLRP3 signaling pathway. Notably, pharmacological inhibition of cGAS with RU.521 replicated the protective effects of BBR. Conclusion: These results demonstrate that BBR alleviates CIRI by attenuating neuroinflammation and oxidative stress via the cGAS‑STING‑NLRP3 axis, thereby identifying a novel mechanism and supporting the traditional use of Coptidis rhizome.