Mitochondrial STING Governs Glycolytic Reprogramming in Diabetic Cardiomyopathy

BACKGROUND: Diabetic cardiomyopathy, a severe complication of diabetes, is marked by mitochondrial dysfunction, metabolic inflammation, and progressive cardiac impairment. Although STING (stimulator of interferon genes) is well recognized as a central mediator of innate immunity, its noncanonical role in metabolic regulation and mitochondrial dynamics in the diabetic heart remains largely unexplored. METHODS: To elucidate the role of STING in diabetic cardiac remodeling, we used single-cell RNA sequencing, echocardiography, and transmission electron microscopy in both genetic (db/db) and chemically induced (high-fat diet [HFD] plus streptozotocin, HFD/streptozotocin) diabetic mouse models. STING knockout mice and primary neonatal mouse cardiomyocytes were used for mechanistic investigations and functional validation. Mitochondrial respiration and glycolytic flux were assessed using Seahorse extracellular flux analysis. Posttranslational modifications of STING, including S -palmitoylation and S -sulfhydration, were evaluated via acyl-biotin exchange and biotin-switch assays, respectively. ENO1 (enolase 1) enzymatic activity was measured in vitro to assess glycolytic reprogramming. Furthermore, 13 C-glucose tracing–based targeted metabolomics was performed to quantify cardiac metabolic flux in db/db mice. Glycolytic metabolites, including lactate and pyruvate, were quantified in cardiac tissues and cultured cardiomyocytes to assess glycolytic activity. RESULTS: Exposure to high-palmitate conditions induced mitochondrial DNA leakage, thereby activating the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway in cardiomyocytes. Mechanistically, STING underwent aberrant translocation to mitochondria, where it interacted with the outer membrane protein TOM (translocase of outer mitochondrial membrane) 40 to impair mitochondrial protein import and disrupt mitochondrial homeostasis. In addition, mitochondrial STING functioned as a scaffold to recruit and activate the glycolytic enzyme ENO1, thereby enhancing its enzymatic activity, accelerating glycolytic flux, and promoting lactate accumulation in diabetic cardiac tissues. Notably, diabetes-associated depletion of endogenous hydrogen sulfide reduced S -sulfhydration of STING at Cys88/91 (cysteine residues 88 and 91 of STING), facilitating its S -palmitoylation and mitochondrial localization. Genetic ablation of STING or pharmacological restoration of hydrogen sulfide levels with GYY4137, a slow-releasing hydrogen sulfide donor, effectively rescued mitochondrial dysfunction, decreased lactate overproduction, and preserved cardiac contractile performance in diabetic mice. CONCLUSIONS: These findings identify STING as a spatial immunometabolic modulator that bridges mitochondrial dysfunction with metabolic imbalance in diabetic cardiomyopathy. Enhancing STING S -sulfhydration or targeting its palmitoylation through hydrogen sulfide–based interventions represents a promising therapeutic strategy for the treatment of diabetic cardiomyopathy.