DUSP6介导的线粒体自噬在拉帕替尼肝脏毒性中的作用及机制研究

EGFR/HER2双靶点酪氨酸激酶抑制剂拉帕替尼，是治疗晚期及转移性乳腺癌的重要药物，但其致死性肝脏毒性严重影响其临床安全有效应用，因此亟需深入开展机制研究寻找潜在干预策略。申请人前期研究发现，拉帕替尼可诱导小鼠肝脏功能异常与肝细胞凋亡，可能通过增强肝细胞SENP1表达，促进DUSP6蛋白的异常降解，进而过度激活肝细胞线粒体自噬，最终导致肝细胞凋亡。基于此，本课题将研究线粒体自噬是否为拉帕替尼肝脏毒性发生的关键原因，探索SENP1调控DUSP6蛋白，异常激活线粒体自噬的分子机制，求证SENP1抑制剂对拉帕替尼肝脏毒性的干预作用。本课题不仅将阐明线粒体自噬促进拉帕替尼肝脏毒性发生的作用模式，还将明确SENP1小分子抑制剂的干预作用，为拉帕替尼的临床安全有效应用提供新策略，也将为其他药物的肝脏毒性研究提供新思路。

Lapatinib, a small-molecule tyrosine kinase inhibitor targeting EGFR and HER2, is the important therapeutic drug for advanced or metastatic breast cancer with significant curative effect. However, the fatal hepatotoxicity severely affects the safe and effective use of lapatinib in clinic. There is an urgent need to study the mechanism and find potential intervention. Preliminary data found that lapatinib could cause liver dysfunction and hepatocytes apoptosis in mice. Lapatinib might promote the abnormal degradation of DUSP6 by increasing the level of SENP1 which then over-activates mitophagy and eventually leads to apoptosis in hepatocytes. Based on this, this study will clarify that mitophagy is the key cause of lapatinib-induced hepatotoxicity, explore the regulatory effect of SENP1 on the stability of DUSP6 and the regulatory mechanism of DUSP6 in lapatinib-induced mitophagy, and verify the intervention effect of SENP1 inhibitor on lapatinib-induced hepatotoxicity. This study will not only clarify the role of mitophagy in promoting the hepatotoxicity of lapatinib, but also demonstrate the intervention effect of SENP1 inhibitor. This study will provide a new strategy for the safe and effective application of lapatinib in clinic and a new direction for the research of hepatotoxicity induced by other drugs.