乐伐替尼作为新一代多靶点酪氨酸激酶抑制剂，是晚期肝癌等实体瘤的一线治疗药物。然而乐伐替尼的致死性心脏毒副反应严重影响其治疗效果与患者生存质量，是临床亟需解决的关键科学问题之一。申请人前期研究发现，乐伐替尼可导致小鼠心功能不全，但乐伐替尼并不直接杀伤心肌细胞，而可能通过阻断CHD7对MHC-II基因转录的抑制，激活血管内皮细胞的抗原呈递活性，诱导TNFα释放，间接引起心肌细胞死亡。基于此，本课题将明确乐伐替尼经由血管内皮细胞诱发心脏毒性的分子过程，发现乐伐替尼对CHD7的调控作用，探索CHD7对MHC-II基因转录与抗原呈递活性的调控机制，确证TNFα的释放及其受体TNFR1与乐伐替尼心脏毒性的相关性。本课题不仅将阐明血管内皮细胞介导的乐伐替尼心脏毒性发生模式，还将明确小分子TNFR1抑制剂的治疗作用，为乐伐替尼的临床安全有效应用提供新策略，也将为其他抗肿瘤药物的心脏毒性研究提供新思路。

Lenvatinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has been approved as the first-line treatment of patients with solid tumors like advanced hepatocellular carcinoma. However, the fatal cardiac side effects of lenvatinib seriously affect the therapeutic effects and the quality of life of patients, which is one of the key scientific problems to be solved in clinic. Preliminary data found that lenvatinib can cause cardiac dysfunction in mice. However, we found that lenvatinib showed no direct cytotoxic effects on cardiomyocyte and it may cause cardiomyocyte death indirectly by blocking CHD7-meidated inhibition on MHC-II gene transcription, activating the antigen presenting activity of vascular endothelial cells, inducing TNFα release. This study will clarify the molecular process of vascular endothelial cells mediated cardiotoxicity of lenvatinib, find out the regulatory effect of lenvatinib on CHD7, explore the regulatory mechanism of CHD7 on MHC-II gene transcription and antigen-presenting activity, and confirm the correlation between TNFα/TNFR1 and lenvatinib-induced cardiotoxicity. This study will not only clarify the model and mechanism of the cardiotoxicity of lenvatinib, but also demonstrate the therapeutic effect of small-molecule TNFR1 inhibitor, provide a new strategy for the long-term safe and effective application of lenvatinib in clinic, and provide a new direction for the research of cardiotoxicity induced by other anti-cancer drugs.