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<p>Pyroptotic inflammation has been shown to contribute to neuronal injury after stroke. Uncoordinated-5 homolog B (UNC5B) is implicated in neuroinflammation, and its downstream kinase death-associated protein kinase 3 (DAPK3) is predicted to interact with mevalonate kinase (MVK). To examine the role of UNC5B in post-stroke pyroptosis, we used a photothrombosis (PT) stroke model in mice and an oxygen-glucose deprivation (OGD) model in BV-2 microglia. Knockdown of <i>Unc5b</i> or <i>Mvk</i> and pharmacological inhibition of DAPK3 were performed, followed by detection of pyroptosis-associated proteins and cell viability. Interactions between DAPK3 and MVK were assessed using transwell coculture and co-immunoprecipitation. PT or OGD induced neuronal injury and increased expression of pyroptosis-related proteins. Knockdown of <i>Unc5b</i> or Mvk in microglia protected neurons by suppressing pyroptosis and disrupting the DAPK3–MVK protein complex. Upregulation of p-MVK was prevented by either <i>Unc5b</i> knockdown or DAPK3 inhibition, whereas DAPK3 upregulation was blocked only by <i>Unc5b</i> knockdown and not by <i>Mvk</i> knockdown. Our results suggest that UNC5B promotes post-stroke microglial pyroptosis in part through the DAPK3/MVK pathway.</p>

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UNC5B Promotes Post-Stroke Microglial Pyroptosis via DAPK3/MVK Pathway

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Ying Luo,
  • Songjie Liao,
  • Meiling Yao,
  • Rui Wang,
  • Jian Yu

摘要

Pyroptotic inflammation has been shown to contribute to neuronal injury after stroke. Uncoordinated-5 homolog B (UNC5B) is implicated in neuroinflammation, and its downstream kinase death-associated protein kinase 3 (DAPK3) is predicted to interact with mevalonate kinase (MVK). To examine the role of UNC5B in post-stroke pyroptosis, we used a photothrombosis (PT) stroke model in mice and an oxygen-glucose deprivation (OGD) model in BV-2 microglia. Knockdown of Unc5b or Mvk and pharmacological inhibition of DAPK3 were performed, followed by detection of pyroptosis-associated proteins and cell viability. Interactions between DAPK3 and MVK were assessed using transwell coculture and co-immunoprecipitation. PT or OGD induced neuronal injury and increased expression of pyroptosis-related proteins. Knockdown of Unc5b or Mvk in microglia protected neurons by suppressing pyroptosis and disrupting the DAPK3–MVK protein complex. Upregulation of p-MVK was prevented by either Unc5b knockdown or DAPK3 inhibition, whereas DAPK3 upregulation was blocked only by Unc5b knockdown and not by Mvk knockdown. Our results suggest that UNC5B promotes post-stroke microglial pyroptosis in part through the DAPK3/MVK pathway.