Liraglutide suppresses ferroptosis by upregulation NRF2 in type 2 diabetic cardiomyopathy

Recent research indicates that inhibiting myocardial ferroptosis may help alleviate diabetic cardiomyopathy (DCM). Liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, has been shown to offer cardiovascular protective effects. Nevertheless, the specific role of LIRA and its relationship with myocardial ferroptosis in type 2 DCM is still not well understood. An in vivo model of type 2 diabetes mellitus (T2DM) was created using spontaneous diabetes Goto-Kakizaki (GK) rats. These rats received LIRA at a dose of 200 μg/kg/day through daily subcutaneous injections for 8 weeks. In vitro experiments involved treating H9C2 cells with different concentrations of glucose, LIRA, siRNA-Nrf2, Fer-1, or their combinations. The results demonstrated that LIRA enhanced glucose metabolism, improved cardiac remodeling and function, reduced lipid peroxidation, and mitigated myocardial ferroptosis in diabetic rats. Additionally, LIRA was found to increase the levels of proteins associated with ferroptosis, such as Cyto-NRF2, Nu-NRF2, PTGS2, FTH-1, and GPX4 in DCM. In vitro, high glucose levels intensified the production of lipid reactive oxygen species (ROS) and lipid peroxidation, diminished mitochondrial mass, and lowered the levels of ferroptosis-related proteins, ultimately triggering ferroptosis. Notably, these detrimental effects were mitigated by LIRA treatment. Overall, these results indicate that LIRA may serve as a valuable therapeutic option for addressing myocardial ferroptosis by promoting NRF2 expression in type 2 DCM.