Abstract

Aims Recent research has shown that the gut microbiota arrests the progression of myocardial infarction (MI) by modulating immune inflammation, oxidative stress, and metabolism. However, the mechanism by which gut-derived trimethylamine N -oxide (TMAO) promotes cardiomyocyte pyroptosis following MI remains unclear. Methods and results We found that a high-choline diet exacerbated cardiac injury in mice by disrupting the intestinal barrier. Under high-choline conditions, the expression levels of tRF-1:31-Glu-TTC-2 (tRF-Glu) derived from tRF and tiRNAs (tsRNAs) were elevated, serving as a key target for intervention in cardiomyocyte pyroptosis. Loss of tRF-Glu significantly ameliorated TMAO-induced deterioration of myocardial fibrosis and cardiac function. Mechanistically, tRF-Glu directly binds to the mitochondrial inner membrane protein ANT1 and stabilizes its expression by inhibiting ubiquitination. Cardiomyocyte knockdown of ANT1 significantly blocked the generation of TMAO-induced cardiomyocyte mitochondrial reactive oxygen species, restored cardiomyocyte membrane potential, and reduced mitochondrial DNA (mtDNA) leakage. Conclusions Our findings indicate that tRF-Glu inhibits the ubiquitination of ANT1 under the induction of TMAO, which in turn activates gasdermin D (GSDMD) and mtDNA release, accelerating cardiac remodeling. In conclusion, our study provides new insights into the role of the gut microbial metabolite-driven tRF-Glu–ANT1–GSDMD pathway in blocking cardiomyocyte pyroptosis and cardiac injury. Graphical abstract The alternative text for this image may have been generated using AI.