Irisin improves diabetic cardiomyopathy-induced cardiac remodeling by regulating GSDMD-mediated pyroptosis through MITOL/STING signaling

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM). However, the mechanisms underlying DCM-induced cardiac injury remain unclear. Recently, the role of Cyclic GMP-AMP Synthase/stimulator of interferon gene (cGAS/STING) signaling and Pyroptosis in DCM has been investigated. Based on our previous results, this study was designed to examine the impact of irisin, mitochondrial ubiquitin Ligase (MITOL/MARCH5), and cGAS/STING signaling in DCM-induced cardiac dysfunction and the effect of gasdermin D (GSDMD)-dependent Pyroptosis. High-fat diet-induced mice and H9c2 cells were used for cardiac geometry and function or pyroptosis-related biomarker assessment at the end of the experiments. Here, we show that DCM impairs cardiac function by increasing cardiac fibrosis and GSDMD-dependent Pyroptosis, including the activation of MITOL and cGAS/STING signaling. Our results confirmed that the protective role of irisin and MITOL was partially offset by the activation of cGAS/STING signaling. We also demonstrated that GSDMD-dependent Pyroptosis plays a pivotal role in the pathological process of DCM pathogenesis. Our results indicate that irisin treatment protects against DCM injury, mitochondrial homeostasis, and Pyroptosis through MITOL upregulation.