USP18 Serves as a Key Mediator of cGAS-STING for Cardiac Aging in Diabetes.

Diabetes accelerates cardiac aging, but the molecular mechanisms that link metabolic stress to myocardial senescence remain insufficiently defined. This study investigated factors driving diabetes-associated cardiac aging with a focus on the role of USP18. Type 2 diabetes mellitus (T2DM) was induced in mice using a high-fat diet combined with streptozotocin. Cardiac structure, function, and molecular alterations were evaluated by echocardiography, histology, RNA sequencing, western blotting, qPCR, and immunofluorescence. H9C2 cardiomyocytes cultured under high-glucose conditions were used for in vitro validation. Diabetic mice exhibited diastolic dysfunction, myocardial hypertrophy, and fibrosis, accompanied by increased p53 and p21 expression. RNA-seq and protein analyses consistently identified USP18 as significantly upregulated in diabetic hearts. Elevated USP18 was associated with activation of the cGAS-STING pathway, increased TBK1 phosphorylation, and enhanced IL-6 and IL-1β production. High-glucose-treated cardiomyocytes similarly showed USP18 induction, stabilization of cGAS-STING signaling, and enhanced senescence-related responses. USP18 contributes to cardiac aging in diabetes by promoting cGAS-STING activation and inflammatory senescence. Targeting USP18 may represent a potential strategy to alleviate myocardial aging under diabetic conditions.