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<p>Butyrate, a microbiota-derived short-chain fatty acid, has been implicated in myocardial protection against ischemia (MI), yet its underlying mechanisms remain incompletely understood. To address this, we generated an MI model in C57BL/6 mice through left anterior descending coronary artery (LAD) ligation. The model demonstrated characteristic myocardial injury, including increased infarct size, elevated lactate dehydrogenase (LDH) release, upregulated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and downregulated NF-E2-related factor 2 (Nrf2). Concomitantly, myocardial pyroptosis was significantly enhanced, as evidenced by elevated expressions of NOD-like receptor pyrin domain-containing 3 (NLRP3), cleaved caspase-1, apoptosis-associated speck-like protein (ASC), and gasdermin D N-terminal fragment (GSDMD-N). Remarkably, butyrate administration reversed all these pathological alterations. Parallel results were validated in human AC16 cardiomyocytes under oxygen–glucose deprivation (OGD) conditions. Mechanistically, butyrate suppressed Nrf2 ubiquitination in cardiomyocytes by inhibiting the MALT1-Nrf2 interaction. Rescue experiments using MALT1 overexpression plasmids demonstrated that butyrate-induced activation of the Nrf2/HO-1 pathway and pyroptosis inhibition were abolished by MALT1 upregulation. Collectively, our findings reveal that butyrate mitigates MI-associated pyroptosis by downregulating MALT1 and stabilizing Nrf2 through inhibition of ubiquitin-dependent degradation.</p>

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Butyrate protects against myocardial ischemia injury and cardiomyocyte pyroptosis by inhibiting MALT1-mediated Nrf2 ubiquitination and degradation

  • 期刊论文

  • 发表日期：

    2025年8月8日

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  • Peipei Zhang,
  • Youli Su,
  • Yi Cheng

摘要

Butyrate, a microbiota-derived short-chain fatty acid, has been implicated in myocardial protection against ischemia (MI), yet its underlying mechanisms remain incompletely understood. To address this, we generated an MI model in C57BL/6 mice through left anterior descending coronary artery (LAD) ligation. The model demonstrated characteristic myocardial injury, including increased infarct size, elevated lactate dehydrogenase (LDH) release, upregulated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and downregulated NF-E2-related factor 2 (Nrf2). Concomitantly, myocardial pyroptosis was significantly enhanced, as evidenced by elevated expressions of NOD-like receptor pyrin domain-containing 3 (NLRP3), cleaved caspase-1, apoptosis-associated speck-like protein (ASC), and gasdermin D N-terminal fragment (GSDMD-N). Remarkably, butyrate administration reversed all these pathological alterations. Parallel results were validated in human AC16 cardiomyocytes under oxygen–glucose deprivation (OGD) conditions. Mechanistically, butyrate suppressed Nrf2 ubiquitination in cardiomyocytes by inhibiting the MALT1-Nrf2 interaction. Rescue experiments using MALT1 overexpression plasmids demonstrated that butyrate-induced activation of the Nrf2/HO-1 pathway and pyroptosis inhibition were abolished by MALT1 upregulation. Collectively, our findings reveal that butyrate mitigates MI-associated pyroptosis by downregulating MALT1 and stabilizing Nrf2 through inhibition of ubiquitin-dependent degradation.