Doxorubicin (DOX) is a chemotherapeutic agent in treating various types of cancers (Rawat et al., 2021, Sawicki et al., 2021, Yarmohammadi et al., 2021). However, the severe dose-dependent side effects on the heart have significantly restricted its use in clinical settings (Zamorano et al., 2016). The incidence of heart failure increases exponentially with cumulative DOX doses (Swain et al., 2003). DOX-induced cardiotoxicity (DIC) can manifest as either acute or chronic. Acute DIC presents as temporary left ventricular dysfunction, arrhythmias, and abnormal electrocardiograms (Zamorano et al., 2016). On the other hand, chronic DIC is characterized as progressive aggravation of cardiac dysfunction (Kong et al., 2022, Wu et al., 2023). Currently, dexrazoxane is proved in multiple clinical trials to exert cardioprotective effects for DIC treatment. It works through various mechanisms, such as chelating labile iron, reducing oxidative stress, and preventing DNA damage (Deng et al., 2014, Wallace et al., 2020). Other treatment options consist of adjusting DOX regimen, antioxidants, utilization of liposomal formulation, and medications to treat cardiac dysfunction (Wenningmann et al., 2019). However, these treatments may not specifically target the specific mechanisms participating in the development of DIC. Therefore, it is essential to explore the crucial pathogenesis of DIC and alternative therapeutic approaches.
Iron is a critical microelement for almost all living organisms. Notably, the significance of iron is particularly pronounced in cardiomyocytes for the high energy demands, where its ability to transport electrons makes it a key player in crucial biochemical reactions (Hentze et al., 2004). Specifically, iron is critical for varieties of cardiovascular functions, such as energy production, formation of heme and iron-sulfur (Fe-S) cluster, and enzyme catalysis for biochemical reactions (Gudjoncik et al., 2014). Nonetheless, iron can exert detrimental effects by catalyzing the formation of reactive oxygen species (ROS) via the Fenton reaction (Sawicki et al., 2023). Besides, excessive iron accumulation can trigger ferroptosis, which is a non-apoptotic regulated cell death (Ahola and Langer, 2024). In this context, iron overload in cardiomyocytes can be detrimental to cardiovascular system. During the last 5 years, multiple studies have demonstrated that DOX treatment causes iron deposit in cardiomyocytes, resulting in lipid peroxidation and ferroptosis, as well as the progression of DIC (Fang et al., 2019, Li et al., 2022, Tadokoro et al., 2020). Furthermore, numerous pharmacological compounds have emerged as potential inhibitors for iron overload and ferroptosis, showing promising therapeutic efficacy in mice with DIC (Fang et al., 2019, Li et al., 2022, Tadokoro et al., 2020, Wang et al., 2022, Zhang et al., 2021). Therefore, dysregulation of iron metabolism and ferroptosis are tightly related to the onset and development of DIC. Here, we will summarize the evidence and mechanisms for dysregulated iron metabolism and ferroptosis involved in DIC; and we will discuss current advances regarding new treatment approaches targeting these pathophysiological processes for DIC.