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Here, the role of lysine lactylation, an epigenetic modification of lactate, in cerebral ischemia is investigated. Using a mouse model of transient middle cerebral artery occlusion, increased brain lactate levels and global protein lactylation are observed. Proteomics analysis reveals significant lactylation of non\u2010histone proteins in the ischemic penumbra. Lactylation of MeCP2, a transcriptional regulator, is identified as a protective mechanism against stroke\u2010induced neuronal death. Inhibition of MeCP2 lactylation through chemical or genetic manipulation increases infarct volume and aggravates neurological deficits. Mechanistically, MeCP2 lactylation at K210\/K249 represses the transcription of apoptosis\u2010associated genes, including\n                    <jats:italic>Pdcd4<\/jats:italic>\n                    and\n                    <jats:italic>Pla2g6<\/jats:italic>\n                    , thereby attenuating neuronal apoptosis. Additionally, HDAC3 and p300 are identified as key enzymes that regulate MeCP2 lactylation post\u2010stroke. The findings suggest that MeCP2 lactylation offers a potential therapeutic target for alleviating neuronal damage and improving stroke outcomes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202415309","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T06:43:01Z","timestamp":1745476981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["MeCP2 Lactylation Protects against Ischemic Brain Injury by Transcriptionally Regulating Neuronal Apoptosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Min","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing 210008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Clinical College of 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