IL-38 attenuates diabetic cardiomyopathy by regulating NLRP3-mediated pyroptosis via the STING signaling pathway.

Diabetic cardiomyopathy (DCM) represents a distinctive myocardial disorder marked by detrimental structural remodeling, encompassing cardiac hypertrophy, myocardial fibrosis, compromised coronary microvascular perfusion, and myocardial dysfunction. Pyroptosis, a newly recognized form of programmed cell death, correlates with inflammatory responses. Chronic inflammation serves a pivotal function in DCM, with pyroptosis substantially contributing to myocardial inflammation in this pathological state. IL-38 demonstrates anti-inflammatory properties through the inhibition of inflammatory signaling pathways in target cells. This investigation sought to examine whether IL-38 could alleviate DM-induced myocardial injury through the modulation of pyroptosis. Following the induction of type 2 diabetes in mice, IL-38 treatment (with or without NLRP3 overexpression) was administered for an additional 8 weeks. Cardiac function, histological architecture, and cardiomyocyte apoptosis underwent assessment. Levels of pyroptosis-related proteins and associated signaling pathways regulating pyroptosis were evaluated. Additionally, the influence of IL-38 on pyroptosis was examined in cultured primary cardiomyocytes. IL-38 demonstrated protective effects against myocardial damage both in vivo and in vitro. The expression levels of pyroptosis-associated proteins increased in type 2 diabetic mice, while IL-38 administration suppressed the pyroptotic process. Additionally, IL-38 reduced pyroptosis via modulation of the STING/NLRP3 signaling cascade. Nevertheless, enhanced NLRP3 expression or STING pathway stimulation counteracted the beneficial outcomes of IL-38.