Phosphorylation‐facilitated CKB lactylation at K11 by GCN5 enhances creatine kinase activity and mitigates neuronal damage after cerebral ischemia‐reperfusion

Duan, Chao, Zhang, Ruolin, Ding, Shihui, Feng, Ying, Shen, Tao, Wang, Ziwei, Bao, Wendai, Shui, Ke, Qin, Jun, Chen, Jun, Zhang, Min, Ren, Zijing, Zhao, Dongmei, Guo, Xingrong, Ai, Zhibing, Yang, Chris ORCID: https://orcid.org/0000-0002-8429-7598, Zhou, Peiyang and Dong, Zhiqiang 2026. Phosphorylation‐facilitated CKB lactylation at K11 by GCN5 enhances creatine kinase activity and mitigates neuronal damage after cerebral ischemia‐reperfusion. Advanced Science 10.1002/advs.202516663

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Abstract

Ischemia-reperfusion (I/R) injury in stroke causes severe neuronal damage through oxidative stress and metabolic dysfunction. 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-type (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-translational modification mechanism that enhances CKB activity and confers neuroprotection in cerebral I/R injury, offering a potential therapeutic target for stroke intervention.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Engineering
Publisher:	Wiley
ISSN:	2198-3844
Date of First Compliant Deposit:	20 July 2026
Last Modified:	20 Jul 2026 15:00
URI:	https://orca.cardiff.ac.uk/id/eprint/188350

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