Oxymatrine Alleviates Cerebral Ischemia/Reperfusion Injury By Targeting HDAC1 to Regulate Mitochondria-Related Autophagy and Oxidative Stress

Abstract Oxymatrine (OMT), a major alkaloid extracted from Sophora flavescens, has been widely recognized for its anti-inflammatory and anti-cancer properties. However, its precise neuroprotective mechanisms in cerebral ischemia/reperfusion (I/R) injury remain to be fully elucidated. In this study, we combined in vivo and in vitro models to investigate the therapeutic effects of OMT on cerebral I/R injury and glutamate-induced neuronal toxicity during the reperfusion process. In vivo, a mouse middle cerebral artery occlusion (MCAO) model was established to recapitulate I/R injury, whereas glutamate-exposed HT22 hippocampal neurons were utilized as an in vitro model to mimic excitotoxic damage. Bioinformatics analysis, integrated with molecular docking, identified histone deacetylase 1 (HDAC1) as a potential direct target of OMT. Subsequent experimental validation demonstrated that OMT attenuates I/R-induced brain damage by modulating HDAC1-mediated pathways involved in autophagy and oxidative stress regulation. OMT treatment significantly reduced infarct volume and improved neurological function in mice. At the cellular level, OMT suppressed mitochondrial apoptosis and reactive oxygen species (ROS) accumulation, restored mitochondrial membrane integrity, and rebalanced mitochondrial dynamics by downregulating fission-related proteins (Fis1) and upregulating fusion markers (Mfn2). Additionally, OMT inhibited excessive autophagy through modulation of the PINK1/Parkin signaling pathway, as evidenced by decreased expression of LC3-II/I ratio, PINK1, Parkin, and NBR1, along with restored levels of P62.These findings suggest that OMT exerts its neuroprotective effects in cerebral I/R injury by targeting HDAC1, thereby alleviating oxidative stress and excessive autophagy. This study provides new mechanistic insights and supports OMT as a promising therapeutic candidate for ischemic stroke treatment. Graphical Abstract