细胞保护蛋白Flip和XIAP在雷公藤甲素增加肝脏对炎性刺激敏感性中的作用及机制研究

雷公藤甲素（TP）是雷公藤中主要的药效成分和毒性成分，免疫抑制是其主要的药效作用，而免疫抑制在雷公藤甲素所致肝损伤中的作用尚不明确。本课题组前期工作发现，TP预处理可以使无毒性剂量的LPS产生严重的肝毒性，提示肝脏对炎性刺激的敏感性显著增强。同时，研究发现TP可以抑制细胞保护蛋白Flip和XIAP的表达，提示TP可能破坏了肝细胞促存活和促死亡信号通路之间的平衡，引起肝脏免疫应答功能失常，从而使肝细胞因无法抵抗炎症刺激而导致死亡。因此，我们提出如下假设：TP通过抑制肝细胞保护蛋白Flip和XIAP抑制促存活信号通路，破坏肝细胞正常免疫应答，增加肝脏对炎性刺激的敏感性，导致肝损伤显著加重。本研究预期阐明TP通过抑制肝脏免疫应答功能增加肝脏受损风险的分子机制，研究结果对于理解TP经免疫抑制介导的肝毒性机制具有重要的科学意义，并为预防及治疗雷公藤类药物肝损伤提供新的思路和作用靶点。

Triptolide (TP) is a main active and toxic component of Tripterygium wilfordii Hook F. Although immunosuppression is regarded as a primary active effect of TP, there is no research focusing on the role of immunosuppression in TP-induced hepatotoxicity. Our previous study showed that a non-toxic dose of LPS could induce severe hepatotoxicity under TP-pretreatment, which revealed an enhanced sensitivity of liver to inflammatory stimuli. Meanwhile, it was found that TP suppressed the expression of cytoprotective proteins Cellular FLICE-inhibitory Protein (Flip) and X-Linked inhibitor of apoptosis protein (XIAP). It indicated that the imbalance between pro-survival and pro-death signaling pathways in hepatocytes might be caused by TP，which induced dysfunction of liver immune response, leading to the death of hepatocytes due to inability to resist inflammatory stimuli. Therefore, We propose the following hypothesis: TP inhibits the pro-survival signaling pathway by inhibiting the hepatocytic protective proteins Flip and XIAP disrupting the normal immune response of hepatocytes, increasing the sensitivity of liver to inflammatory stimuli, which finally results in a significant increase in liver damage. This study is expected to clarify the molecular mechanism of TP-raised risk of liver injury by inhibiting the immune response of liver. This study has great value for understanding the mechanism of TP-induced hepatotoxicity by immunosuppression. It provide a new perspective and effect target for the prevention and treatment of Tripterygium wilfordii induced liver injury.