作为BCR-Abl第二代抑制剂，达沙替尼现已成为治疗CML的一线药物，但高达4%充血性心衰发生率限制了其长期安全使用，确切机制尚未阐明。我们前期研究发现，达沙替尼主要通过程序性坏死(Necroptosis)诱导心肌细胞死亡，在这过程中，死亡受体通路中的RIP3扮演了举足轻重的角色，而RIP3发挥作用受其Neddylation这一全新修饰方式的调控。基于此，本课题将进一步明确心肌细胞程序性坏死在达沙替尼心脏毒性中的作用，确证RIP3蛋白的去Neddylation修饰作为关键环节在此过程中的调控作用，阐明达沙替尼调控RIP3蛋白去Neddylation修饰分子过程，并进一步探索去Neddylation酶抑制剂作为达沙替尼心脏毒性干预策略的可行性。通过本课题的研究，不仅将阐明达沙替尼心脏毒性的分子机制，发现RIP3蛋白全新的翻译后修饰方式及其调控机制，还可为临床克服达沙替尼的心脏毒性提供新策略。

As the second generation of BCR-Abl inhibitor, Dasatinib was approved for first-line treatment of chronic myeloid leukemia. However over 4% incidence of cardiotoxicity limits its clinical application, and the molecular mechanism remains unclear. We previously found that dasatinib could induce myocardial cell death via necroptosis. And this type of necroptosis was relied on RIP3, which was mediated by deneddylation. Based on this findings, we will first clarify the role of myocardial cell necroptosis in dasatinib-induced cardiotoxicity. Furthermore, we will identify the mechanism of dasatinib-mediated RIP3 deneddylation in this process. In addition, we will confirm the possibility of potential RIP3 deneddylation inhibitor as intervention strategy for dasatinib-induced cardiotoxicity. Taken together, this study will not only illustrate the molecular mechanism of dasatinib-induced cardiotoxicity and the novel post-translational modification of RIP3, but also provide a new strategy for overcoming dasatinib-induced cardiotoxicity.