阿霉素是一种广谱高效的抗肿瘤药物，因其剂量依赖的心脏毒性限制了临床应用。而目前临床可用的保护剂右丙亚胺效果有限，因此完善阿霉素心脏毒性分子机制的研究，并在此基础上寻找新的保护剂就显得非常紧迫。我们的前期研究发现Nrf2/DJ-1蛋白复合物可负性调控阿霉素诱导的心肌细胞凋亡，并据此筛选发现了新型黄酮类Nrf2/DJ-1复合物稳定剂ZMY，体内外实验显示能显著降低阿霉素的心脏毒性，可使小鼠阿霉素造模组的存活率从7.69%提高至84.62%，且对阿霉素的抗肿瘤作用没有影响。与右丙亚胺相较，ZMY显示出极大的优越性。本项目将在此基础上，进一步研究明确Nrf2/DJ-1蛋白复合物负性调控阿霉素心脏毒性的作用及分子过程，进而丰富抗肿瘤药物诱发心脏毒性的基础理论；同时全面评价ZMY保护阿霉素心脏毒性的作用，并探寻其干预作用的分子机制和关键因子，为研发阿霉素心脏毒性的保护药物提供崭新的思路。

Doxorubicin, a highly effective anticancer drug, produces dose-related cardiotoxicity, which limits its therapeutic potential. The search for cardioprotective agents that alleviate doxorubicin cardiotoxicity in the last 30 years has led only to dexrazoxane. However,the possibility of its interference with the tumor response rate to the doxorubicin treatment and higher incidence of myelodysplastic syndrome increase the anxiety of clinicians to use dexrazoxane. To get clinically effective protectors,the study on novel mechanism of doxorubicin-induced cardiotoxicity becomes more emergent. Our previous data shown that Nrf2/DJ-1 complex play a new and important role in doxorubicin-induced cardiotoxicity. The novel flavonoid named ZMY got from Nrf2/DJ-1 complex inhibition screen, indicated complete protection against doxorubicin-induced cardiotoxicity in vitro and in vivo. Our results showed that ZMY could significantly increase survival rate from 7.69% to 84.62% in mice with doxorubicin treatments. What's more, ZMY enhanced doxorubicin-induced anticancer activity in vitro and in vivo. It was indicated that ZMY had the much better perspective than dexrazozane as a potential clinical protector against doxorubicin-induced cardiotoxicity. In this study, we will identify the role and mechanism that Nrf2/DJ-1 complex negative regulate doxorubicin-induced cardiotoxcity, which to enrich the theory of anticancer agents-induced cardiotoxicity. More importantly, to evaluate the protection and mechanism of ZMY in doxorubicin-induced cardiotoxicity that can provide new sight for cardiotoxicity prevention research.