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Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta\u2010hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood\u2010brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO\u2010ketogenesis processes by administration of CPT1\u03b1 antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO\u20101 by enhancing local \u03b2\u2010hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO\u2010ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.<\/jats:p>","DOI":"10.1002\/advs.202400426","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T05:49:09Z","timestamp":1714110549000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Adaptive Metabolic Responses Facilitate Blood\u2010Brain Barrier Repair in Ischemic Stroke via BHB\u2010Mediated Epigenetic Modification of ZO\u20101 Expression"],"prefix":"10.1002","volume":"11","author":[{"given":"Ruijie","family":"Li","sequence":"first","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat\u2010Sen University  Guangzhou 510080 China"},{"name":"National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine 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