Mechanisms of doxorubicin-induced cardiac inflammation and fibrosis; therapeutic targets and approaches

Doxorubicin plays a pivotal role in the treatment of various malignancies. Despite its efficacy, the cardiotoxicity associated with doxorubicin limits its clinical utility. The cardiotoxic nature of doxorubicin is attributed to several mechanisms, including its interference with mitochondrial function, the generation of reactive oxygen species (ROS), and the subsequent damage to cardiomyocyte DNA, proteins, and lipids. Furthermore, doxorubicin disrupts the homeostasis of cardiac-specific transcription factors and signaling pathways, exacerbating cardiac dysfunction. Oxidative stress, cell death, and other severe changes, such as mitochondrial dysfunction, activation of pro-oxidant enzymes, the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress, and infiltration of immune cells in the heart after treatment with doxorubicin, may cause inflammatory and fibrotic responses. Fibrosis and inflammation can lead to a range of disorders in the heart, resulting in potential cardiac dysfunction and disease. Various adjuvants have shown potential in preclinical studies to mitigate these challenges associated with cardiac inflammation and fibrosis. Antioxidants, plant-based products, specific inhibitors, and cardioprotective drugs may be recommended to alleviate cardiotoxicity. This review explores the complex mechanisms of doxorubicin-induced heart inflammation and fibrosis, identifies possible cellular and molecular targets, and investigates potential substances that could help reduce these harmful effects.