Protective effects of biomimetic Cu-Zn-MOF against DOX-Induced cardiotoxicity through inhibiting oxidative stress and ferroptosis

Background: Doxorubicin (DOX), a member of the anthracycline family, is widely recognized as an effective chemotherapeutic agent for cancer treatment. However, its clinical application is limited due to its cardiotoxicity. Targeting reactive oxidative stress (ROS) and ferroptosis provides an approach to attenuate DOX-induced cardiotoxicity (DIC). Methods: A biomimetic metal-organic framework, Cu-Zn-MOF (CZM), was synthesized and evaluated for its enzyme-mimicking activities and biosafety. The therapeutic effects of CZM on oxidative stress, ferroptosis, and myocardial injury were assessed both in vitro and in vivo. Results: The synthesized CZM exhibited efficient enzyme-mimicking activities for ROS scavenging. Additionally, CZM showed high iron-chelating efficiency. In vitro, CZM protects cardiomyocytes from oxidative stress and ferroptosis. In mouse models of acute or chronic DIC, CZM administration showed superior myocardial protective effects compared to Dexrazoxane, a clinical drug approved for DIC treatment. These effects were evidenced by improved cardiac function and structural remodeling. Mechanistically, CZM enhanced the expression of mitochondrial respiratory complexes, maintained mitochondrial homeostasis, and inhibited iron overload. Furthermore, CZM reduced the activation of the AMPK/mTOR signaling pathway and suppressed DOX-triggered ferroptosis. Conclusion: In all, our study demonstrates that CZM possesses excellent enzyme-mimicking activities, along with good biosafety and biocompatibility. These findings highlight CZM’s potential as a novel cardioprotective drug for mitigating DIC.