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Beyond its metabolic role, lactate can induce lysine lactylation, but its impact on neuroprotection remains unclear. Here, we employed integrative proteomic, lactylomic, and phosphoproteomic profiling in a murine I\/R model and identified creatine kinase B\u2010type (CKB) as a dual target of K11 lactylation and S199 phosphorylation. These modifications were found to enhance CKB enzymatic activity, promote phosphocreatine metabolism, suppress reactive oxygen species, and support neuronal survival under ischemic conditions. Mechanistically, the acetyltransferase GCN5 catalyzed K11 lactylation, while Sirt5 functioned as a delactylase. Notably, S199 phosphorylation facilitated K11 lactylation by promoting GCN5 recruitment, suggesting a hierarchical interplay between the two modifications. In vivo studies confirmed that disruption of either K11 lactylation or S199 phosphorylation impaired CKB function, exacerbated neuronal injury, and delayed functional recovery after stroke. These findings reveal a coordinated post\u2010translational modification mechanism that enhances CKB activity and confers neuroprotection in cerebral I\/R injury, offering a potential therapeutic target for stroke intervention.<\/jats:p>","DOI":"10.1002\/advs.202516663","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:06:07Z","timestamp":1784325967000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylation\u2010Facilitated CKB Lactylation At K11 By GCN5 Enhances Creatine Kinase Activity and Mitigates Neuronal Damage After Cerebral Ischemia\u2010Reperfusion"],"prefix":"10.1002","volume":"13","author":[{"given":"Chao","family":"Duan","sequence":"first","affiliation":[{"name":"Hubei Provincial Clinical Research Center of Central Nervous System Repair and Functional Reconstruction Taihe Hospital Hubei University of Medicine Shiyan Hubei China"},{"name":"College of 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