YBX3通过稳定PKM2蛋白及激活mTOR-HIF-1α信号通路，增强小胶质细胞糖酵解水平，从而加剧缺血再灌注损伤。

Abstract

Stroke remains one of the leading causes of death and long-term disability worldwide, with neuroinflammation and metabolic dysfunction playing central roles in its pathogenesis. In this study, we investigated the function of Y-box binding protein 3 (YBX3) in ischemic stroke, with particular focus on its regulation of glycolysis and neuroinflammatory responses. Using a middle cerebral artery occlusion (MCAO) model in C57BL/6 mice and an oxygen-glucose deprivation/reperfusion (OGD/R) model in BV2 microglia, we observed that YBX3 expression was markedly upregulated following ischemia-reperfusion. Overexpression of YBX3 aggravated cerebral infarct size, worsened motor and neurological outcomes, and increased the release of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) both in vivo and in vitro. Mechanistically, YBX3 enhanced glycolysis in BV2 cells by stabilizing pyruvate kinase M2 (PKM2) mRNA and promoting its expression, while simultaneously activating glycolysis through the mTOR-HIF-1α signaling pathway. Pharmacological inhibition of mTOR with rapamycin reversed YBX3-induced glycolytic activation, neuroinflammation, and neuronal injury. Collectively, these results identify YBX3 as a key regulator of ischemic brain damage through glycolysis-dependent mechanisms and underscore its potential as a therapeutic target for stroke.