基于生物信息学探讨疏肝降脂颗粒调节铁死亡治疗非酒精性脂肪性肝病的作用

Study on the Molecular Mechanism of Shugan Jiangzhi Granules Regulating Ferroptosis in the Treatment of Non-alcoholic Fatty Liver Disease

本研究旨在运用生物信息学方法探讨疏肝降脂颗粒调节铁死亡治疗非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)的潜在分子机制。通过网络药理学方法获取“疏肝降脂颗粒-铁死亡”潜在的交集靶点,基于GSE89632数据集筛选“疏肝降脂颗粒-NAFLD-铁死亡”交集靶点的差异表达基因(differentially expressed genes,DEGs),并运用R4.2.2软件进行相关性分析、富集分析和免疫浸润分析。对GSE89632数据集的样本进行共识聚类,构建机器学习模型,筛选关键DEGs,构建列线图模型并验证;对关键基因进行临床相关性分析。共获得18个“疏肝降脂颗粒-NAFLD-铁死亡”DEGs,富集在Th17细胞分化、甲状腺激素信号通路、ErbB信号通路、IL-17信号通路等方面。随机森林(random forest,RF)模型为最优机器学习模型,AURKA、SREBF1、HMOX1、MYC和JUN是RF模型中重要性排名前五的基因,HMOX1、JUN与体重指数(body mass index,BMI)呈正相关。列线图模型可以较好地预测NAFLD患病风险。本研究发现疏肝降脂颗粒调节铁死亡治疗NAFLD可能是通过AURKA、SREBF1、HMOX1、MYC和JUN等差异铁死亡基因之间的网络调控作用及其介导的免疫调节,以及Th17细胞分化、甲状腺激素信号通路、ErbB信号通路和IL-17信号通路等途径实现的。基于AURKA、SREBF1、HMOX1、MYC和JUN的列线图模型不但能够较准确地诊断NAFLD,而且可以间接评估疏肝降脂颗粒治疗NAFLD的效能。

To explore the possible molecular mechanism of Shugan Jiangzhi granules in regulating ferroptosis in the treatment of non-alcoholic fatty liver disease(NAFLD)by using the method of bioinformatics.The potential intersection targets of"Shugan Jiangzhi granules-ferroptosis"were obtained by network pharmacology.The differentially expressed genes(DEGs)of the intersection target of"Shugan Jiangzhi granules-NAFLD-ferroptosis"were screened based on the GSE89632 dataset,and the correlation analysis,enrichment analysis and immune infiltration analysis were performed by using R4.2.2 software.The samples of GSE89632 dataset were clustered and typed,the machine learning model was constructed to screen the key genes of DEGs,and the risk prediction nomogram model was constructed and verified.The clinical correlation of key genes was analyzed.Finally,a total of 18 DEGs of"Shugan Jiangzhi granules-NAFLD-ferroptosis"were obtained.DEGs enriched in Th17 cell differentiation,thyroid hormone signaling pathway,ErbB signaling pathway,IL-17 signaling pathway and so on.Random forest(RF)model is the optimal machine learning model.AURKA,SREBF1,HMOX1,MYC and JUN were the top five genes in the RF model.HMOX1 and JUN were positively correlated with body mass index(BMI).Nomogram model has good predictive ability for the risk of NAFLD.This study suggests that Shugan Jiangzhi granules can regulate ferroptosis to treat NAFLD through network regulation of AURKA,SREBF1,HMOX1,MYC,JUN and other differentially expressed ferroptosis-related genes,and mediated immune regulation,Th17 cell differentiation,thyroid hormone signaling pathway,ErbB signaling pathway,IL-17 signaling pathway.The nomogram model based on AURKA,SREBF1,HMOX1,MYC and JUN can not only accurately diagnose NAFLD,but also indirectly evaluate the efficacy of Shugan Jiangzhi granule in the treatment of NAFLD.