High Uric Acid Orchestrates Ferroptosis to Promote Doxorubicin-Induced Cardiomyopathy via ROS-GPX4 Signaling

Abstract

Abstract Background: Doxorubicin (DOX) is a chemotherapeutic drug that induces cardiotoxicity known as doxorubicin -induced cardiomyopathy(DIC). Studies have confirmed that DOX can cause cardiac damage via ferroptosis. High uric acid (HUA), as a pro-oxidant, participates in the pathophysiology of cardiovascular disease. Epidemiological studies suggest elevated uric acid levels can have detrimentaleffects on cardiovascular disease. However, the effect of hyperuricemia in a specific type of cardiomyopathy, DIC, is unclear. It is unknown if HUA exacerbates DIC and if the tumor patients with hyperuricemia will aggravate the cardiac side effects of DOX. Methods: In uricase knockout (Uox-/-) mice, we explored the effect of HUA on DOX-induced cardiotoxicity, including cardiac function, pathomorphology, and its mechanism. Results: We demonstrated that Uox-KO mice accelerated the development of DIC, causing significantly impaired cardiac function and myocardial fibrosis. Meanwhile, the mitochondrial morphology was destroyed, the lipid peroxidation products increased in number and the antioxidant function was weakened. In addition, we evaluated the effects of ferrostatin-1 (Fer-1), the ferroptosis inhibitor. Myocardial damage can be reversed by the Fer-1 treatment caused by HUA combined with DOX treatment. Benzbromarone, a UA-lowering drug, decreases myocardial fibrosis and ferroptosis by alleviating hyperuricemia in Uox-KO mice by DOX administration. In vitro, we observed that the activity of cardiomyocytes treated with HUA combined with DOX decreased significantly, and lipid reactive oxygen species (ROS) increased significantly. Afterwards, we demonstrated that HUA can promote oxidative stress in DOX, characterised by increased mitochondrial ROS, and down-regulate protein levels of glutathione peroxidase 4 (GPX4). N-acetyl-L-cysteine, an antioxidant, inhibits the process by which HUA promotes DOX-induced ferroptosis by increasing the GPX4 expression. Conclusions: Our data suggested that HUA promotes the DIC. And HUA promotes DOX-induced ferroptosis by increasing oxidative stress and down-regulating GPX4. It is implied that tumor patients with hyperuricemia may increase cardiac side effects when taking DOX during chemotherapy treatment.