Circular RNA-OGDH promotes PANoptosis in diabetic cardiomyopathy: A novel mechanistic insight

Diabetic cardiomyopathy is a myocardial structural and functional abnormality directly caused by diabetes and is a principal factor in the development of cardiovascular complications in patients with diabetes. The study aims to investigate the role of circOGDH in the development of DCM and elucidate its precise underlying mechanisms. We established two well-characterized diabetic mouse models, C57BL/6J and db/db, and assessed cardiac function by serum lactate dehydrogenase activity assay and echocardiography, as well as quantitative histological analyses of the extent of myocardial fibrosis in combination with HE staining and Masson trichrome staining. The results demonstrated that there was a significant upregulation of circOGDH expression levels in myocardial tissues of mice in a diabetic state, accompanied by the increased expression of key effector proteins of PANoptosis. It is noteworthy that the knockdown of circOGDH led to a substantial enhancement in cardiac function indices, a reduction in the area of myocardial fibrosis, and the effective inhibition of the PANoptosis process in myocardial tissues. In the H9c2 cells model, silencing of circOGDH also exhibited significant protective effects, including increased cell survival, reduced levels of oxidative stress, decreased apoptosis, and suppressed expression of PANoptosis-related proteins. Subsequent employing RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation experimental methods have elucidated, for the first time, the molecular mechanism by which circOGDH specifically targets and regulates RIPK3 through the HMGB1 signaling pathway. The present study definitively demonstrated that upregulation of circOGDH expression in a diabetic state could exacerbate pathological damage in DCM by activating the HMGB1-RIPK3 signaling pathway.