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<p>Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m<sup>6</sup>A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m<sup>6</sup>A reader protein YTHDF2, which recognizes m<sup>6</sup>A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.</p>

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Dexmedetomidine inhibits microglia activation, neuroinflammation, and glycolysis in postoperative cognitive dysfunction by promoting YTHDF2-mediated PKM2 mRNA degradation

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Qianyu Li,
  • Huiyue Wang,
  • Nan Chen,
  • Xue Liu,
  • Yongle Li,
  • Lei Chen,
  • Lu Gan,
  • Yong Luan

摘要

Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m6A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m6A reader protein YTHDF2, which recognizes m6A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.