急性肝损时花生四烯酸类前炎性物质(AAs)的代谢异常，以CYP/UGT代谢调控内源性分子失衡为切入点是新的抗炎策略。我们研究冬凌草甲素抗肝炎机制时新发现LXR-CYP4F/UGT调控通路可显著影响AAs代谢，而冬凌草甲素可上调CYP4F/UGT从而逆转LPS所致的AAs异常升高。推测冬凌草甲素通过LXR-CYP4F/UGT通路调控AAs代谢平衡，缓解肝损症状。申请人拟结合转录组和基因组完善LXR参与AAs的代谢调控网络；利用过表达/沉默HepG2、THP-1及人原代肝细胞，采用LXRs等基因敲除小鼠，从体内体外确证LXR-CYP4F/UGT-AAs的代谢调控通路；同时结合药物PK/PD参数揭示冬凌草甲素通过上述通路抗炎的体内代谢物质基础。本项目将从平衡内源性分子AAs代谢的角度，深入诠释CYP/UGT代谢调控参与冬凌草甲素治疗急性肝损的新机制，旨在为靶向代谢调控的创新药物研发提供新策略。

The CYP and UGT mediated metabolism of arachidonic acid and its inflammatory metabolites (AAs) were abnormal in liver during acute liver injury (ALI). We previously found that oridonin can significantly reduce the acute liver injury induced by LPS in mice. A novel LXR-CYP4F/UGT regulation pathway of AAs metabolism was found. The AAs metabolism by CYP4Fs and the conjugation mediated by UGTs, as well as liver X receptor (LXR) were both up regulated after administration of Oridonin. In order to confirm the therapeutic effect on ALI through LXR-CYP4F/UGT-AAs regulation pathway by Oridonin, this project aims to: 1) Explore the individual human hydroxylation and glucuronidation of AAs in human liver microsomes, and establish the CYP/UGT regulation network based on the availability of genome sequence and basal RNA-seq data from human livers using bioinformatics. 2) Explore the relationship between cellular inflammation and the metabolic regulation of AA and its pro-inflammatory metabolites through LXR regulation pathway in vitro by using gene-overexpressing or knockout HepG2 cells, THP-1 cells, and human primary hepatocytes; 3) Explore the anti-inflammatory key factors via the metabolic regulation of AAs in vivo using LXR knockout mice model, as well as the PK/PD model to further demonstrate our hypothesis. This study can develop new thoughts for the treatment and approaches of acute hepatitis based on metabolism regulation of endogenous, and can provide the theory and experimental data for clinical use of oridonin.