Finerenone ameliorates high-fat-induced myocardial lipotoxicity by suppressing ferroptosis through augmenting the...

Obesity cardiomyopathy (OCM) is a distinct clinical entity in cardiovascular disease, yet targeted therapeutic options are scarce. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, has shown cardioprotective effects, but its role in mitigating OCM lipotoxicity is unclear. To elucidate the underlying functions and mechanisms, rats were fed on an HFD for 16 weeks to establish the OCM model. At the 12th week of HFD, the OCM rats were administered 10 mg/kg finerenone for 4 weeks. Cardiac ultrasound, glycolipid metabolism, lipid deposition, histopathology, and oxidative stress were evaluated in rats to elucidate the effects of finerenone on myocardial lipotoxic injury phenotype in relation to cardiac function and structure. Additionally, we identified potential mechanisms by which finerenone ameliorates lipotoxicity using cardiac tissue's RNA sequencing technology and bioinformatics analyses. Furthermore, the efficacy and underlying mechanisms of finerenone were validated using an in vitro cardiomyocyte model of lipotoxic injury induced by high palmitate stimulation in H9C2 cells. Finerenone treatment did not affect body weight or insulin resistance but significantly ameliorated cardiac hypertrophy, diastolic dysfunction, and myocardial lipotoxicity in HFD-induced obese rats. Transcriptome analyses revealed that finerenone significantly suppressed the ferroptosis pathway in the hearts of HFD-treated rats. Further studies demonstrated that finerenone attenuated ferroptosis by activating the System Xc^- transporter, enhancing cellular cystine uptake, promoting intracellular glutathione (GSH) synthesis, and thus restoring redox balance in cardiomyocytes. Finerenone alleviates myocardial lipotoxicity in HFD-induced obese rats by inhibiting ferroptosis through the regulation of the System Xc^-/GSH axis. Finerenone may prove an effective treatment for OCM.