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<p>Prior studies have indicated that the neuroprotective effects of dexmedetomidine (DEX) in cerebral ischemia, yet its mechanisms remain elusive. Using multi-omics approaches (RNA-seq, metabolomics, and single-cell RNA-seq), we discovered that DEX pretreatment significantly reduced cerebral infarct volume and improved neurological function in middle cerebral artery occlusion (MCAO) mice compared to PBS controls. Single-cell analysis revealed that DEX preserved microglial phagocytic function via metabolic regulation, leading to reduced microglial apoptosis and attenuated immune dysregulation—including decreased chemotactic neutrophils, B cells, and antigen-presenting fibroblasts. These cellular changes were corroborated by transcriptomic and metabolic profiles showing suppressed apoptosis and inflammation. Mechanistically, we identified HK2 (hexokinase 2) as a key regulator of microglial homeostasis, with its expression correlating with microglial migration, proliferation, and inflammation, findings validated in oxygen–glucose deprivation models. Collectively, our results demonstrate that DEX protects against cerebral ischemia–reperfusion injury by maintaining immune microenvironment homeostasis through microglial metabolic reprogramming mediated by HK2. This multi-omics study provides mechanistic insights supporting DEX’s translational potential in ischemic stroke therapy.</p>

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Single-Cell RNA-Seq Revealed the Immune Microenvironment Reprogramming by Dexmedetomidine Treatment in Ischemic Stroke

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Wenyi Zhang,
  • Xingyun Wang,
  • Bing Zhang,
  • Minjiang Yi,
  • Yinzhong Lu,
  • Shuyan Wang,
  • Junfeng Zhang,
  • Guangming Zhang

摘要

Prior studies have indicated that the neuroprotective effects of dexmedetomidine (DEX) in cerebral ischemia, yet its mechanisms remain elusive. Using multi-omics approaches (RNA-seq, metabolomics, and single-cell RNA-seq), we discovered that DEX pretreatment significantly reduced cerebral infarct volume and improved neurological function in middle cerebral artery occlusion (MCAO) mice compared to PBS controls. Single-cell analysis revealed that DEX preserved microglial phagocytic function via metabolic regulation, leading to reduced microglial apoptosis and attenuated immune dysregulation—including decreased chemotactic neutrophils, B cells, and antigen-presenting fibroblasts. These cellular changes were corroborated by transcriptomic and metabolic profiles showing suppressed apoptosis and inflammation. Mechanistically, we identified HK2 (hexokinase 2) as a key regulator of microglial homeostasis, with its expression correlating with microglial migration, proliferation, and inflammation, findings validated in oxygen–glucose deprivation models. Collectively, our results demonstrate that DEX protects against cerebral ischemia–reperfusion injury by maintaining immune microenvironment homeostasis through microglial metabolic reprogramming mediated by HK2. This multi-omics study provides mechanistic insights supporting DEX’s translational potential in ischemic stroke therapy.