Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion

  • Commun Biol. 2024 Dec 26;7(1):1701. doi: 10.1038/s42003-024-07425-6.
Wei-Yue Si  1 ,  Chun-Lin Yang  2  3  4 ,  Shu-Li Wei  1 ,  Tong Du  2  3  4 ,  Liang-Kang Li  1 ,  Jing Dong  2 ,  Yang Zhou  2 ,  Heng Li  2  3  4 ,  Peng Zhang  2  3  4 ,  Qi-Ji Liu  5 ,  Rui-Sheng Duan  1  2  3  4 ,  Ruo-Nan Duan  6
Affiliations
  • 1. Department of Neurology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
  • 2. Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, PR China.
  • 3. Shandong Institute of Neuroimmunology, Jinan, People's Republic of China.
  • 4. Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, People's Republic of China.
  • 5. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 6. Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China. [email protected].
PMID: 39725685 DOI: 10.1038/s42003-024-07425-6
Abstract

Acute ischemic stroke (AIS) triggers immune responses and neuroinflammation, contributing to brain injury. Histone lactylation, a metabolic stress-related histone modification, plays a critical role in various diseases, but its involvement in cerebral ischemia remains unclear. This study utilized a transient middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) model to investigate the role of microglial histone lactylation in ischemia-reperfusion injury. Lactate overload post-AIS increased histone lactylation, while reduced SMEK1 expression in microglia correlated with elevated lactate and neuroinflammation. Microglia-specific SMEK1 deficiency enhanced lactate production by inhibiting the pyruvate dehydrogenase kinase 3-pyruvate dehydrogenase (PDK3-PDH) pathway, increasing H3 lysine 9 lactylation (H3K9la), activating Ldha and HIF-1α transcription, and promoting glycolysis. SMEK1 overexpression improved neurological recovery in ischemic mice. This study highlights SMEK1 as a novel regulator of histone lactylation and a potential therapeutic target for mitigating neuroinflammation and enhancing recovery after AIS.

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