Interplay of oxidative stress and inflammatory mechanisms in doxorubicin-induced cardiomyopathy

Doxorubicin (DOX) is a potent chemotherapeutic drug used to treat a variety of cancer types, but its usage is limited due to major cardiovascular side effects. According to World Health Organization reports, by 2050, new cancer cases are projected to increase to >35 million, implying an enhanced risk of DOX-induced cardiomyopathy (DIC). Despite its cardiotoxic side effects, DOX has remained an effective therapeutic choice for cancer treatment. Current evidence suggests that multiple pathophysiological mechanisms are involved in DIC, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium dysregulation, and inflammation, all of which lead to cardiac cell death and disease progression. Recently, several oxidative stress- and inflammation-mediated signaling pathways, including mitogen-activated protein kinase, high-mobility group box 1/TLR4, nuclear factor kappa B, NOD-like receptor protein 3 (NLRP3) inflammasome, Janus kinase-signal transducer and activator of transcription, and tumor necrosis factor alpha, have been identified as contributing factors to cardiac remodeling in DIC. Although significant progress has been made over the past two decades in understanding the pathophysiological mechanisms of DIC, the exact mechanism leading to DIC remains unclear. Hence, in this review, we discuss various types of immune cells, including neutrophils, monocytes, and macrophages, cellular and molecular pathological mechanisms of inflammation, and various types of cell death in DIC. Furthermore, we discuss how understanding the significance of inflammatory mechanisms may enhance therapeutic efficacy and inform future perspectives.