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

Abstract

ABSTRACT 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.