What is the clinical evidence from this study?

Study design: Other. Population: Myocardial infarction. Intervention: Dnmt3a overexpression (AAV9-Dnmt3a) or Caspase-8 inhibition (Z-IETD-fmk) vs. Negative control (AAV9-NC) or sham operation. Primary outcome: Cardiac function (ejection fraction and fractional shortening) and cardiomyocyte pyroptosis.

What question did this study set out to answer?

To investigate the role of Caspase-8 and the effect of Dnmt3a on cardiomyocyte pyroptosis during myocardial infarction.

April 24, 2026Nature Communications0 citationsOpen Access

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

NWNing WangHarbin Medical University LGLiling GongHarbin Medical University XZXingmiao ZhaoHarbin Medical University

Key Result

Targeted inhibition of Caspase-8 or overexpression of Dnmt3a significantly improved left ventricular systolic function and reduced cardiomyocyte pyroptosis in male mice following myocardial infarction.

Key Points

To investigate the role of Caspase-8 and the effect of Dnmt3a on cardiomyocyte pyroptosis during myocardial infarction.
Examined the Caspase-8/Gsdmd signaling pathway in male infarcted mice
Inhibited Caspase-8 to assess cardiac function recovery
Analyzed Dnmt3a's impact on Caspase-8 transcription and cardiac protection
Caspase-8 activation contributes to cardiomyocyte pyroptosis post myocardial infarction
Inhibition of Caspase-8 improves cardiac function after MI
Dnmt3a regulates Caspase-8 expression through DNA methylation, with its reduction linked to increased ubiquitination

Structured PICO

Does modulation of the Dnmt3a/Caspase-8/Gsdmd axis reduce cardiomyocyte pyroptosis and improve cardiac function in a mouse model of myocardial infarction?

Population

Male mice subjected to acute myocardial infarction via left anterior descending (LAD) coronary artery ligation for 24 hours, and neonatal mouse ventricular cardiomyocytes (NMVCs).

Intervention

AAV9-mediated Caspase-8 overexpression (AAV9-CMV-GFP-Caspase-8), cardiomyocyte-specific Gsdmd knockout (Gsdmd-CKO), Caspase-8 inhibitor Z-IETD-fmk (4 mg/kg IV) combined with necrostatin-1 (3.5 mg/kg IV), and AAV9-mediated Dnmt3a overexpression (AAV9-CMV-GFP-Dnmt3a).

Comparator

Sham-operated controls, negative control AAV9 (AAV9-CMV-GFP), Gsdmd-flox mice (Gsdmdflox/flox), and vehicle controls.

Outcome

Cardiomyocyte pyroptosis (measured by Gsdmd cleavage, LDH release, IL-1β, and IL-18) and cardiac function (ejection fraction and fractional shortening via echocardiography).surrogate

This study identifies the Dnmt3a/Caspase-8/Gsdmd axis as a key mechanism driving cardiomyocyte pyroptosis post-myocardial infarction, highlighting potential new epigenetic and molecular therapeutic targets for ischemic heart disease.

Abstract

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.

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