Vericiguat as a Novel Ferroptosis Inhibitor Alleviates Doxorubicin-Induced Cardiotoxicity.

Abstract

BACKGROUND AND PURPOSE: Doxorubicin is a widely used chemotherapy drug, but its clinical application is limited by dose-dependent cardiotoxicity, known as doxorubicin-induced cardiomyopathy (DIC), for which no specific therapies currently exist. Vericiguat, a soluble guanylate cyclase agonist, has shown significant cardiovascular protective effects. However, its role and the underlying molecular mechanisms in DIC remain unclear. EXPERIMENTAL APPROACH: We established both in vivo and in vitro models of DIC. In the in vivo experiments, cardiac function in male wild-type C57BL/6 mice was evaluated through echocardiography, measurement of serum CK-MB and cTnT, and histological examinations. For the in vitro studies, cardiomyocyte viability was assessed by CCK-8 assay and PI/Hoechst staining. To evaluate ferroptosis, the accumulation levels of iron, reactive oxygen species (ROS), and lipid peroxides in cardiomyocytes were assessed using FerroOrange staining, DCFH-DA fluorescent probe, and MDA content measurement, respectively. The expression levels of ferroptosis-related markers SLC7A11 and GPX4 were examined by Western blot. KEY RESULTS: Vericiguat significantly alleviated cardiac injury induced by doxorubicin by lowering oxidative stress and inhibiting ferroptosis and directly counteracted cardiomyocyte injury induced by the ferroptosis activator erastin. CONCLUSION AND IMPLICATIONS: These findings indicate that vericiguat protects against doxorubicin-induced myocardial ferroptosis, positioning it as a promising therapeutic candidate for DIC and a novel ferroptosis inhibitor.