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<p>Aspartate-specific cysteine protease (Caspase)-8 plays a critical role in initiating pyroptosis by mediating cleavage and activation of gasdermin-D (Gsdmd) during Yersinia infection. However, the role of Caspase-8 in pyroptosis after myocardial infarction (MI) and its underlying mechanism remains elusive. Here we show that Caspase-8 is essential for cardiomyocyte pyroptosis post MI and Caspase-8/Gsdmd signaling pathway is activated in hearts of male infarcted mice. The inhibition of Caspase-8 in male mice rescues the decline of cardiac function and cardiomyocyte pyroptosis following MI. Dnmt3a is further shown to impact DNA methylation on the CpG island of <i>Caspase-8</i> promoter and regulate Caspase-8 expression. Dnmt3a overexpression protects myocardium from MI in male mice by inhibiting cardiomyocyte pyroptosis. Moreover, reduction of Dnmt3a in MI is attributed to the increased ubiquitination. Our study identifies a regulatory axis, Dnmt3a/Caspase-8/Gsdmd, which drives ischemic heart injury by promoting cardiomyocyte pyroptosis, and suggests potential therapeutic targets for heart diseases.</p>

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Loss of DNA methyltransferase 3a enhances Caspase-8 transcription and promotes cardiomyocyte pyroptosis during myocardial infarction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Ning Wang,
  • Liling Gong,
  • Xingmiao Zhao,
  • Wenshuang Zhao,
  • Ning Xu,
  • Ximing Chen,
  • Qingwei Zhang,
  • Ming Li,
  • Yijing Yao,
  • Hang Yu,
  • Qingsui Li,
  • Zhen Zhang,
  • Liwei Zhu,
  • Long Qin,
  • Xu Su,
  • Zhen Zhang,
  • Wei Li,
  • Wanyu Zhang,
  • Yadong Xue,
  • Xianzhi Lang,
  • Pengyu Li,
  • Sijia Li,
  • Siyu Chang,
  • Jiamin Li,
  • Benzhi Cai

摘要

Aspartate-specific cysteine protease (Caspase)-8 plays a critical role in initiating pyroptosis by mediating cleavage and activation of gasdermin-D (Gsdmd) during Yersinia infection. However, the role of Caspase-8 in pyroptosis after myocardial infarction (MI) and its underlying mechanism remains elusive. Here we show that Caspase-8 is essential for cardiomyocyte pyroptosis post MI and Caspase-8/Gsdmd signaling pathway is activated in hearts of male infarcted mice. The inhibition of Caspase-8 in male mice rescues the decline of cardiac function and cardiomyocyte pyroptosis following MI. Dnmt3a is further shown to impact DNA methylation on the CpG island of Caspase-8 promoter and regulate Caspase-8 expression. Dnmt3a overexpression protects myocardium from MI in male mice by inhibiting cardiomyocyte pyroptosis. Moreover, reduction of Dnmt3a in MI is attributed to the increased ubiquitination. Our study identifies a regulatory axis, Dnmt3a/Caspase-8/Gsdmd, which drives ischemic heart injury by promoting cardiomyocyte pyroptosis, and suggests potential therapeutic targets for heart diseases.