Abstract

Background and Purpose Doxorubicin has been used widely for the treatment of human cancer but its clinical use is limited by cardiotoxicity. We examined the effect of the pan-NADPH oxidase inhibitor Vas2780 on myocyte ferroptosis and cardiac remodelling and function in a clinically relevant mouse model of chronic doxorubicin-induced cardiomyopathy and the underlying mechanisms. Experimental Approach Sixty-five mice were randomized to receive saline, Vas2870 (2 mg·kg −1 , i.p., once a day for 40 days), doxorubicin (3 mg·kg −1 , i.p., every other day, six times) or doxorubicin plus Vas2870 ( n = 10–22). Key Results Doxorubicin-treated mice exhibited a decrease in left ventricular (LV) fractional shortening and an increase in the ratio of lung wet-to-dry weight, indicating LV systolic dysfunction and lung congestion, and these alterations were prevented by the Vas2870 treatment. In doxorubicin-treated mice, myocardial levels of gp91phox, malondialdehyde and 4-hydroxynonenal were increased; SLC7A11, GPX4, FTH1 and FPN proteins were decreased; TfR1 (CD71) protein and myocardial iron levels were elevated and ALAS1 was reduced. Vas2870 inhibited myocardial lipid peroxidation, prevented decreased SLC7A11 and GPX4 proteins, normalized dysregulated iron metabolism-related proteins, increased ALAS1 protein and upregulated mitochondrial genes, resulting in the prevention of iron overload and ferroptosis in doxorubicin-induced cardiomyopathy. Similarly, Vas2870 prevented doxorubicin-induced ferroptosis in H9C2 cardiomyocytes. Conclusion and Implications Vas2870 prevents myocyte ferroptosis through inhibition of lipid peroxidation, GPX4/SLC7A11 downregulation and disruptions in iron metabolism, leading to the amelioration of doxorubicin-induced heart failure. Therapies directed at inhibiting NADPH oxidase and/or ferroptosis may be of value in the treatment of heart failure.