Table1_A gene expression profile-based approach to screen the occurrence and predisposed host characteristics of drug-induced liver injury: a case study of Psoralea corylifolia Linn.docx

Drug-induced liver injury (DILI) is one of the most common causes of a drug being withdrawn, and identifying the culprit drugs and the host factors at risk of causing DILI has become a current challenge. Recent studies have found that immune status plays a considerable role in the development of DILI. In this study, DILI-related differentially expressed genes mediated by immunoinflammatory cytokines were obtained from the Gene Expression Omnibus (GEO) database to predict the occurrence of DILI (named the DILI predictive gene set, DILI_PGS), and the predictability of the DILI_PGS was verified using the Connectivity Map (CMap) and LiverTox platforms. The results obtained DILI_PGS from the GEO database could predict 81.25% of liver injury drugs. In addition, the Coexpedia platform was used to predict the DILI_PGS-related characteristics of common host diseases and found that the DILI_PGS mainly involved immune-related diseases and tumor-related diseases. Then, animal models of immune stress (IS) and immunosuppressive (IP) were selected to simulate the immune status of the above diseases. Meanwhile, psoralen, a main component derived from Psoralea corylifolia Linn. with definite hepatotoxicity, was selected as an experimental drug with highly similar molecular fingerprints to three idiosyncratic hepatotoxic drugs (nefazodone, trovafloxacin, and nimesulide) from the same DILI_PGS dataset. The animal experiment results found a single administration of psoralen could significantly induce liver injury in IS mice, while there was no obvious liver function change in IP mice by repeatedly administering the same dose of psoralen, and the potential mechanism of psoralen-induced liver injury in IS mice may be related to regulating the expression of the TNF-related pathway. In conclusion, this study constructed the DILI_PGS with high accuracy to predict the occurrence of DILI and preliminarily identified the characteristics of host factors inducing DILI.

药物诱导性肝损伤（DILI）是导致药物撤回的最常见原因之一，识别致病的药物及易引发DILI的宿主因素已成为当前的一大挑战。近期研究指出，免疫功能状态在DILI的发生发展中起着至关重要的作用。本研究从基因表达综合数据库（GEO）中获取了由免疫炎症细胞因子介导的DILI相关差异表达基因，用以预测DILI的发生（命名为DILI预测基因集，DILI_PGS），并利用连通性图谱（CMap）和LiverTox平台验证了DILI_PGS的预测能力。从GEO数据库中获得的DILI_PGS能够预测81.25%的肝损伤药物。此外，利用Coexpedia平台预测了DILI_PGS与常见宿主疾病的相关特征，发现DILI_PGS主要涉及免疫相关疾病和肿瘤相关疾病。随后，选取免疫应激（IS）和免疫抑制（IP）动物模型来模拟上述疾病的免疫功能状态。同时，选取了补骨脂（Psoralea corylifolia Linn.）的主要成分补骨脂素作为实验药物，其分子指纹与DILI_PGS数据集中三种特异肝毒性药物（奈法唑酮、 trovafloxacin和尼美舒利）高度相似。动物实验结果表明，单次给予补骨脂即可显著诱导IS小鼠的肝损伤，而重复给予相同剂量的补骨脂在IP小鼠中并未观察到明显的肝功能变化，补骨脂诱导IS小鼠肝损伤的潜在机制可能与调节TNF相关通路的表达有关。综上所述，本研究构建了具有高准确性的DILI_PGS以预测DILI的发生，并初步确定了诱导DILI的宿主因素特征。