Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.Īlthough improved treatments have been effective in increasing the survival of patients with tumors, an increase in the number of side effects of cancer treatment have led to mortality ( 1, 2). Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METT元, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. 5State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, ChinaĬyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment.4Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences (CAS), Beijing, China.3Beijing Lab for Cardiovascular Precision Medicine, Anzhen Hospital, Capital Medical University, Beijing, China.2State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Key Laboratory of Application of Pluripotent Stem Cells in Heart Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.1Department of Cardiology and Institute of Vascular Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China.Min Zhu 1,2 † Yangong Liu 1 † Yuanxiu Song 1 Shiqin Zhang 1 Chengwen Hang 1 Fujian Wu 3 Xianjuan Lin 1 Zenghui Huang 4 Feng Lan 2,3 Ming Xu 1,5 *
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