镉是广泛存在于生产与生活环境中的剧毒重金属污染物，肝脏是其毒理作用的靶器官，但镉肝毒理分子机制仍亟待于研究。我们前期研究发现镉暴露诱导L02细胞自噬流发生，自噬抑制剂3-MA可以显著拮抗镉肝细胞毒性，提示自噬过度活化可能在镉肝毒性中发挥了重要作用。同时，随着镉诱导细胞自噬水平的增高，细胞内ZKSCAN3逐渐降低。基于ZKSCAN3在维护自噬-溶酶体途径稳定的重要性，我们假设镉暴露通过减少肝细胞中ZKSCAN3的表达和激活MAPK通路而提高ZKSCAN3蛋白的磷酸化，促进其向细胞质转位等两方面削弱 ZKSCAN3-DNA的结合能力，从而刺激下游自噬-溶酶体途径基因的转录，诱导肝细胞自噬过度活化。并通过过表达ZKSCAN3，从而稳定自噬-溶酶体途径，抑制线粒体丢失，改善细胞能量代谢拮抗镉肝毒性。本项目研究有望揭示镉肝毒理作用的细胞靶点及分子机制，为开展镉肝毒性治疗和药物的研究提供实验依据。

Cadmium (Cd) , a heavy metal, is an environmental and industrial pollutant with high cytotoxicity, and liver is the main target organ of toxicity of Cd. However, the mechanism of Cd-induced hepatotoxicity needs to clarify. Our previous study indicated that Cd exposure significantly increased autophagic flux in L02 cells , and the autophagy inhibitor 3-MA blocked abnormal autophagy and subsequently ameliorated Cd-induced hepatotoxicity in vitro，indicating that autophagy plays a pivotal role in Cd-mediated hepatotoxicity. In line with the observed autophagic flux induction, the levels of ZKSCAN3 decreased in a dose-dependent manner. In the light of the important roles of ZKSCAN3 in the autophagy–lysosome machinery, we suppose that Cd may decrease ZKSCAN3 mRNA and protein expression, or induced ZKSCAN3 phosphorylation through activation of MAPK signaling pathway, subsequently activated ZKSCAN3 cytoplasmic translocation, which inhibit the ability of ZKSCAN3 binds to CLEAR elements and enhance autophagy-related genes expression in Cd-induced hepatotoxicity. Moreover, we will pay much attention to hepatocyte-specific expression of ZKSCAN3 to protect against Cd-induced hepatotoxicity by maintained the integrity of autophagy–lysosome machinery, inhibited mitochondrial loss, and sustained the ATP levels. Through this study, we would like not only to investigate the novel mechanism underlying the hepatotoxicity of Cd, but also to provide the potential strategy for protecting against the hepatotoxicity of Cd.