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Lysine lactylation, an epigenetic modification in which lactate\u2010derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke\u2010induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl\u2010CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic\/inflammatory genes, especially hexokinase 2 (HK2). HK2 overexpression mimics lactylation\u2010induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)\/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2\u2010K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2\u2010K210 lactylation as a critical metabolic\u2010epigenetic switch driving microglial activation via the HK2\/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.<\/jats:p>","DOI":"10.1002\/advs.202513400","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T03:46:16Z","timestamp":1766461576000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Flipping the Switch: MeCP2\u2010Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2\/mTOR Axis in Poststroke Neuroinflammation"],"prefix":"10.1002","volume":"13","author":[{"given":"Zengyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology of Minhang Hospital State Key Laboratory of Brain Function and Disorders MOE Frontiers Center for Brain Science, and Institutes of Brain Science Fudan University Shanghai 200032 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