Interplay of ferroptosis, cuproptosis, and PANoptosis in cancer treatment-induced cardiotoxicity: Mechanisms and therapeutic implications

With the prolonged survival of individuals with cancer, the emergence of cardiovascular diseases (CVD) induced by cancer treatment has become a significant concern, ranking as the second leading cause of death among cancer survivors. This review explores three distinct types of programmed cell death (PCD): ferroptosis, cuproptosis, and PANoptosis, focusing on their roles in chemotherapy-induced cardiotoxicity. While ferroptosis and cuproptosis are triggered by excess iron and copper (Cu), PANoptosis is an inflammatory PCD with features of pyroptosis, apoptosis, and necroptosis. Recent studies reveal intricate connections among these PCD types, emphasizing the interplay between cuproptosis and ferroptosis. Notably, the role of intracellular Cu in promoting ferroptosis through GPX4 is highlighted. Additionally, ROS-induced PANoptosis is influenced by ferroptosis and cuproptosis, suggesting a complex interrelationship. This review provides insights into the molecular mechanisms of these PCD modalities and their distinct contributions to chemotherapy-induced cardiotoxicity. Furthermore, we discuss the potential application of cardioprotective drugs in managing these PCD types. This comprehensive analysis aims to advance the understanding, diagnosis, and therapeutic strategies for cardiotoxicity associated with cancer treatment.