一线抗结核药吡嗪酰胺（PZA）因药源性肝损伤（DILI）限制了其临床应用。目前DILI机制研究多局限于药物及其代谢产物自身细胞毒作用，但确切机制尚不明确。本项目组前期研究结果提示患者使用PZA所致肝损伤与胆汁酸代谢重排有关，提出FXR-胆汁酸代谢网络与PZA肝毒性之间调控的假说，本课题拟首先通过靶向代谢组学观察细胞、动物及患者不同水平发生DILI时内源性胆汁酸谱的变化规律；再在细胞、小鼠模型中研究PZA对FXR-代谢酶-转运体的表达调控，进一步通过基因敲除小鼠、过表达及沉默等基因调控技术及化学干预的方法揭示FXR-胆汁酸通路调控PZA所致DILI发生的分子机制；最终建立DILI的信号通路与胆汁酸互动调控的网络关系，通过胆汁酸的早期变化预测患者中PZA发生DILI的可能性。本项目不仅可阐释PZA发生DILI新的分子机制，同时为临床安全应用PZA提供新的依据，为预防DILI的研究提供新思路。

Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity. Therefore, severe hepatotoxic side effects have limited PZA therapy for tuberculosis in clinic. However, the exact toxic mechanism underlying these toxicities remains unknown. Our research suggested that patients with PZA induced liver injury associated with rearrangement of bile acid. We hypothesized that FXR-bile acid mediate the hepatotoxicity of PZA. This project utilized targeted metabolomics to observe the changes of endogenous bile acids in cells, animals, and patients when generated DILI. Regulation of metabolism enzymes and transporter continued being studied. Then the mechanism underlies the hepatotoxicity of pyrazinamide mediated by FXR-bile acid was revealed using gene regulation and chemical intervention, such as knockout mice or overexpressed technology. Finally, the regulated network was built between DILI and bile acid, evaluated the potential prediction ability of DILI based on bile acid in baseline plasma. The project can not only provide a new molecular mechanism of DILI, but also provide evidence for the clinical application of PZA and new ideas for prevention of drug-induced liver injury.