吉非替尼是目前临床应用最多的酪氨酸激酶抑制剂之一，但因其严重的肝脏毒性常造成部分患者中断治疗，甚至个别患者的死亡，而针对其毒性机制的研究目前尚无报道，更缺乏有效的干预手段。我们前期研究发现，吉非替尼诱导肝脏损伤后所产生的应激性自噬能拮抗其毒性，提示如能促进这种自噬可成为毒性干预的新策略。进一步研究发现IKKa可调控自噬的激活，参与拮抗吉非替尼肝毒性。基于此，我们将深入研究自噬介导的受损线粒体清除在拮抗吉非替尼肝脏毒性中的作用，探索IKKa与自噬相关蛋白calpain、Beclin 1的相互作用及调控机制，阐明IKKa调控自噬拮抗吉非替尼肝脏毒性的分子机制，进而明确IKKa作为拮抗吉非替尼肝脏毒性潜在靶点的可行性。通过本课题的研究，不仅可发现IKKa的新生物学功能，丰富自噬发生的调控机制，还可为寻找干预吉非替尼肝脏毒性的新策略提供理论依据。

As a wide used, oral, targeted inhibitor of the EGFR kinase, gefitinib is approved for the treatment of non-small cell lung cancer patients to first-line therapy. However, serious liver dysfunction causes some patients to discontinue the medication, even die. The molecular mechanisms responsible for these effects remain largely unknown. Previous study, we showed for the first time that autophagy is induced in vivo and in vitro by clinically relevant doses of gefitinib, which was consistent with the formation of liver damage. Of note, pharmacological or biological autophagy inhibition exacerbated gefitinib-induced liver failure, suggesting that autophagy may act as a self-defense mechanism to promote survival. Interestingly, gefitinib increased the activity of IKKa, which may be a critical modulator of autophagy related to gefitinib-induced liver injury. Based on this, in this study, it will be further performed to determine the role of autophagy in gefitinib-induced hepatotoxicity by cleaning up the damaged mitochondria. What's more, to clarify the possibility that IKKa?works as the molecular target of gefitinib-induced hepatotoxicity therapy, we will explore the effect of IKKa?in autophagy-mediated liver injury with gefitinib treatment and the relationship and molecular mechanism between IKKa, calpain and Beclin 1. Through this study, it will reveal a protective role for autophagy via IKKa signaling in gefitinib-stimulated hepatotoxicity, which provides a novel mechanism for the prevention of drug-induced liver damage. Importantly, IKKa?angonist attenuated gefitinib-induced liver failure, which highlights novel avenues for managing the clinic applications of gefitinib.