Tongmai Yangxin Pill ameliorates doxorubicin-induced cardiotoxicity through m6A/ALKBH5/BNIP3 axis

ETHNOPHARMACOLOGICAL RELEVANCE Cardiotoxicity caused by doxorubicin (DOX) has become the most important toxicity that hinders its clinical application. Tongmai Yangxin (TMYX) Pill is a Chinese patent medicine composed of the ancient classic prescriptions Zhiguorice decoction and Shengmai powder. AIM OF THE STUDY The present study aimed to investigate whether and how TMYX ameliorated the DOX-induced cardiotoxicity via an m6A-dependent mechanism. MATERIALS AND METHODS CCK-8, JC-1 fluorescence mitochondrial membrane potential analysis, ROS fluorescence, TUNEL assay, and oxygen consumption rate assays were performed to evaluate the protective effects of TMYX on cardiomyocytes which were treated with DOX. RESULTS In vivo, TMYX administration effectively improved cardiac function and restored mitochondrial function. For the cardiomyocytes in vitro, TMYX alleviated the cardiomyocytes' apoptosis by recovering mitochondrial energy metabolism that was repressed by DOX treatment. Besides, TMYX reduced the m6A methylation level and promoted m6A demethylase ALKBH5 expression in DOX-treated cardiomyocytes. Mechanistically, TMYX repressed the BNIP3 mRNA stability in an ALKBH5/m6A-dependent manner to improve cardiomyocytes mitochondrial energy metabolism. CONCLUSION These findings illustrated a remarkable protective role of TMYX against DOX-induced cardiotoxicity through ameliorating cardiomyocyte mitochondrial energy metabolism, which provided a new perspective for the mechanism of Chinese medicine compound in the treatment of cardiotoxicity.