Integrated multi-omics analysis reveals the molecular mechanisms of renal denervation in alleviating diabetic cardiomyopathy

Background & Objective Diabetic cardiomyopathy (DCM) is defined as myocardial remodeling and/or dysfunction attributable to diabetes in the absence of coronary artery disease, hypertension, or valvular disease, and it is a major cause of death in people with diabetes [1–3]. Its pathogenesis remains incompletely understood, and no disease-specific therapy is currently available. In recent years, excessive activation of the sympathetic nervous system has been shown to promote myocardial apoptosis, inflammation, and fibrosis, playing a critical role in the progression of DCM. Renal denervation (RDN), an emerging interventional therapy, has demonstrated certain efficacy in the treatment of hypertension and may exert protective effects against DCM by reducing sympathetic nervous activity. Nevertheless, its underlying mechanisms require further elucidation. This study aims to elucidate the molecular basis by which RDN improves cardiac structure and function in DCM through integrated multi-omics analysis and to identify key signaling pathways and potential therapeutic targets. Methodologies Eight-week-old male C57BL/6J mice were divided into control (CT), diabetic cardiomyopathy (DCM), and renal sympathetic denervation (RDN) groups. Diabetes was induced by high-fat diet and STZ, followed by bilateral chemical RDN in the treatment group. After 22 weeks, assessments included glucose metabolism, cardiac function (echocardiography, exercise testing), and histological, ultrastructural, and molecular analyses. Integrated transcriptomic and proteomic profiling of left ventricular tissue was performed to identify key targets and pathways. Result RDN partially improved glucose tolerance and insulin sensitivity, and significantly enhanced cardiac function (increased LVEF, LVFS; reduced LVDd, LVDs, NT-proBNP; improved E/A ratio and exercise capacity). It alleviated cardiomyocyte hypertrophy, interstitial fibrosis, mitochondrial damage, and reduced IL-6 and IL-1β levels. Multi-omics revealed RDN-regulated changes enriched in pathways linked to MHC class I antigen presentation, T-cell activation, and DNA damage response, indicating suppressed immune activation and extracellular matrix remodeling. Conclusion RDN significantly improved cardiac function in DCM mice and reduced myocardial hypertrophy and fibrosis. These changes were accompanied by downregulation of inflammatory and immune pathways, suggesting a cardioprotective mechanism involving suppression of MHC-I/T cell–mediated autoimmunity and extracellular matrix remodeling.