Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion
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 ut...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07425-6 |
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| author | Wei-Yue Si Chun-Lin Yang Shu-Li Wei Tong Du Liang-Kang Li Jing Dong Yang Zhou Heng Li Peng Zhang Qi-Ji Liu Rui-Sheng Duan Ruo-Nan Duan |
| author_facet | Wei-Yue Si Chun-Lin Yang Shu-Li Wei Tong Du Liang-Kang Li Jing Dong Yang Zhou Heng Li Peng Zhang Qi-Ji Liu Rui-Sheng Duan Ruo-Nan Duan |
| author_sort | Wei-Yue Si |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f6b1a90be92c40d490122cc95a13a343 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-f6b1a90be92c40d490122cc95a13a3432024-12-29T12:41:09ZengNature PortfolioCommunications Biology2399-36422024-12-017111710.1038/s42003-024-07425-6Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusionWei-Yue Si0Chun-Lin Yang1Shu-Li Wei2Tong Du3Liang-Kang Li4Jing Dong5Yang Zhou6Heng Li7Peng Zhang8Qi-Ji Liu9Rui-Sheng Duan10Ruo-Nan Duan11Department of Neurology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Neurology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Neurology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Shandong First Medical UniversityKey Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Neurology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Neurology, Qilu Hospital of Shandong UniversityAbstract 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.https://doi.org/10.1038/s42003-024-07425-6 |
| spellingShingle | Wei-Yue Si Chun-Lin Yang Shu-Li Wei Tong Du Liang-Kang Li Jing Dong Yang Zhou Heng Li Peng Zhang Qi-Ji Liu Rui-Sheng Duan Ruo-Nan Duan Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion Communications Biology |
| title | Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion |
| title_full | Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion |
| title_fullStr | Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion |
| title_full_unstemmed | Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion |
| title_short | Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion |
| title_sort | therapeutic potential of microglial smek1 in regulating h3k9 lactylation in cerebral ischemia reperfusion |
| url | https://doi.org/10.1038/s42003-024-07425-6 |
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