Praeruptorin A screened by a ferrous ion probe inhibited DMT1 and ferroptosis to attenuate Doxorubicin-induced cardiomyopathy

Abstract

Doxorubicin (DOX)-induced cardiomyopathy (DIC) greatly limits its clinical application of the anticancer drug. Therefore, there is an immediate necessity to undertake intervention studies to minimize DIC, encompassing the screening of regulatory compounds and delving into the underlying regulatory mechanisms. A growing body of research suggests that ferroptosis is an essential process in the development of DIC. Here, we demonstrated that DOX causes elevated iron levels in cardiomyocytes and mouse hearts, and leads to ferroptosis and cardiac insufficiency. Next, we performed high-throughput screening of a library of herbal small molecule compounds for novel compounds that inhibit ferroptosis, using Fe²⁺ levels as a screening index for DIC prevention and treatment drugs. We found that Praeruptorin A (PA) was able to reduce Fe²⁺ concentration in cardiomyocytes, inhibit ferroptosis, and alleviate DIC and cardiac dysfunction in mice. Concurrently, PA exhibits a synergistic effect with DOX in suppressing the proliferation of carcinoma of breast MCF-7 cell in nude mice. Mechanistically, we found that PA inhibited the expression of divalent metal transporter protein 1 (DMT1), suppressed Fe²⁺ overload in cardiomyocytes, and inhibited ferroptosis, thereby alleviating DIC. Our study demonstrated the feasibility of high-throughput screening targeting the Fe²⁺ concentration, and elucidated the role and mechanism of PA in alleviating DIC, which provides a new possibility.