Vericiguat as a Novel Ferroptosis Inhibitor Alleviates Doxorubicin-Induced Cardiotoxicity

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.

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.

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.

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.