Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The
cyclic GMP-AMP synthase (cGAS)-stimulator of
interferon genes (
STING) signaling pathway has been suggested to contribute to the pathogenesis of
cardiovascular diseases. However, whether cGAS-
STING is involved in the development of DCM has not been established. Our study aimed to determine the role of cGAS-
STING in the initiation of
nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)
inflammasome-induced cardiac pyroptosis and chronic
inflammation during the pathogenesis of DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically knock down myocardial
STING. After four weeks, mice with myocardium-specific knockdown of
STING received
injections of
streptozotocin (STZ; 50 mg/kg) and a high-fat diet to induce diabetes. Measurements included echocardiography, immunohistochemical analyses,
wheat germ agglutinin (WGA) staining, and western blotting. Here, we showed that the cGAS-
STING signaling pathway was activated in diabetic hearts, which was indicated by the increased phosphorylation of TANK-binding
kinase 1 (TBK1) and
interferon (
IFN) regulatory factor 3 (IRF3), leading to the activation of the NLRP3
inflammasome in the hearts of diabetic mice and proinflammatory
cytokine release into serum. Moreover,
STING knockdown via adeno-associated virus-9 (AAV9) in diabetic mouse heart alleviated cardiac pyroptosis and the inflammatory response, prevented diabetes-induced
hypertrophy, and restored cardiac function. Mechanistically, we showed that
palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive mitochondrial
reactive oxygen species (mtROS), which results in oxidative damage to
mitochondrial DNA (
mtDNA) and its release into the cytoplasm while switching on cGAS-
STING-mediated pyroptosis in cardiomyocytes, thereby worsening the progression of
diabetic cardiomyopathy. Our study demonstrated that activation of the cGAS-
STING pathway caused by mitochondrial oxidative damage and
mtDNA escape induced by
free fatty acids promoted pyroptosis and proinflammatory responses in cardiomyocytes in a NLRP3
inflammasome-dependent manner, thus promoting myocardial
hypertrophy during the progression of DCM.