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journal article·2025-06Open access

MeCP2 Lactylation Protects against Ischemic Brain Injury by Transcriptionally Regulating Neuronal Apoptosis

Min Sun, Yuxin Zhang, Rui Mao, Yan Chen, Pinyi Liu, Lei Ye, Siyi Xu, Junqiu Jia, Shu Shu, Huiya Li, Yanping Yin, Shengnan Xia, Yanting Chen, Yun Xu

Advanced Science· Volume 12· Issue 21
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Source abstract

Abstract

Abstract Lactate plays diverse roles in brain pathophysiology, including ischemic stroke. 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‐histone proteins in the ischemic penumbra. Lactylation of MeCP2, a transcriptional regulator, is identified as a protective mechanism against stroke‐induced 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‐associated genes, including Pdcd4 and Pla2g6, thereby attenuating neuronal apoptosis. Additionally, HDAC3 and p300 are identified as key enzymes that regulate MeCP2 lactylation post‐stroke. The findings suggest that MeCP2 lactylation offers a potential therapeutic target for alleviating neuronal damage and improving stroke outcomes.
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Research context

OpenAlex topics: Genetics and Neurodevelopmental Disorders · Adenosine and Purinergic Signaling · Nuclear Receptors and Signaling

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing 210008 China

Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine Nanjing 210008 China

State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing University Nanjing 210008 China

Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases Nanjing University Nanjing 210008 China

Jiangsu Provincial Key Discipline of Neurology Nanjing 210008 China

Nanjing Neurology Clinical Medical Center and Nanjing Gulou Hospital Brain Disease and Brain Science Center Nanjing 210008 China

Nanjing Drum Tower Hospital Clinical College of Jiangsu University Nanjing 210008 China

Department of Neurology Nanjing Drum Tower Hospital Chinese Academy of Medical Science & Peking Union Medical College Nanjing 210008 China

Funding

National Natural Science Foundation of China

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