Adaptive Metabolic Responses Facilitate Blood‐Brain Barrier Repair in Ischemic Stroke via BHB‐Mediated Epigenetic Modification of ZO‐1 Expression

• DOI: 10.1002/advs.202400426
• Publication Date: 2024-04-26T09:49:09Z
• Authors: Ruijie Li; Yilin Liu; Jihao Wu; Xiong Chen; Qiying Lu; Kai Xia; Congyuan Liu; Xin Sui; Yixuan Liu; Yiling Wang; Yuan Qiu; Jinsi Chen; Yi Wang; Ruijun Li; Yucheng Ba; Jiayun Fang; Weijun Huang; Zhengqi Lu; Yanbing Li; Xinxue Liao; Andy Peng Xiang; Yinong Huang
• Keywords: Ketogenesis; Stroke

Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is noted modifiable risk factor recent research suggests that it benefits neurological rehabilitation. During the early phase experimental lipidomic results showed fat depots underwent pronounced lipolysis released fatty acids (FAs) feed into consequent hepatic FA oxidation ketogenesis. Systemic supplementation with predominant ketone beta-hydroxybutyrate (BHB) found to exert discernible effects on preserving blood-brain barrier (BBB) integrity facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage aggravated stroke severity, whereas BHB blunted these injuries. Mechanistically, unveiled infusion taken up monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium upregulated expression tight junction protein ZO-1 enhancing local β-hydroxybutyrylation H3K9 at promoter TJP1 gene. Conclusively, an adaptive mechanism elucidated which acute stimulates restore BBB after stroke. Ketogenesis functions as responder restrain progression, providing novel prospectives clinical translation.