Doxorubicin-induced cardiotoxicity: Is ferroptosis the primary driver or a downstream amplifier?

Doxorubicin (Dox) is one of the most effective anticancer agents used to treat a wide range of solid tumors as well as hematological malignancies. However, its associated cardiotoxicity poses a major challenge for its therapeutic use. There are numerous studies exploring the underlying cellular mechanisms behind Dox-induced cardiotoxicity. Apart from the well-established apoptosis and necrosis pathways, ferroptosis is a recently identified regulated cell death pathway being studied in the context of drug-induced cardiotoxicity. Under normal physiology, cardiomyocytes maintain a highly regulated iron homeostasis, while the polyunsaturated fatty acid-rich membrane also renders it susceptible to peroxidation, a hallmark of ferroptosis. Dox-induced cardiotoxicity disrupts the coordinated control of iron metabolism, generating reactive oxygen species, propagating lipid peroxidation, and impairing mitochondrial function. Progressive structural damage and functional loss of cardiomyocytes culminate in permanent cardiac cell death. Therefore, targeting regulatory nodes of ferroptosis may be beneficial for ameliorating Dox-induced cytotoxicity. However, it is still not clear whether the ferroptotic process merely acts as an initiator or can further act as an amplifier to upregulate the downstream signaling molecules in this cell death cascade. This review offers an overview of perspectives on the ferroptotic pathway and introduces readers to a novel driver-amplifier concept. See also the graphical abstract(Fig. 1).