Discovery of Zidovudine as a cardiomyocyte protectant for doxorubicin-induced toxicity through high-throughput phenotypic drug screening

Doxorubicin (DOX) constitutes a cornerstone in cancer chemotherapy, yet its administration is associated with dose-dependent toxicity to the heart, known as doxorubicin-induced cardiotoxicity (DOX-IC). Presently, dexrazoxane stands as the sole approved drug for mitigating DOX-IC; however, its clinical application is restricted due to concerns over severe adversary effects. It is therefore urgent to discover alternative drug candidates to ameliorate DOX-IC. Here, we report the discovery of Zidovudine (ZIDO), a clinically available anti-retroviral medication, as a potent candidate to protect against DOX-IC both in vitro and in vivo by high-throughput phenotypic screening of a library of 1804 Food and Drug Administration (FDA)-approved drugs. Transcriptomic analysis reveals that ZIDO treatment significantly alleviates DOX-induced dysregulation of genes associated with cardiac function and proteotoxic stress. This study sets a paradigm towards discovering novel cardiac protective drugs through repurposing and establishes ZIDO as an agent holding promise for the treatment of DOX-IC patients.