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

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.