目的 通过网络药理学及分子对接技术挖掘陈皮通过理气功效治疗代谢相关脂肪性肝病的关键有效成分及作用靶点与通路，以探究其可能的药效物质基础及潜在的分子机制。方法 通过中药系统药理学数据库和分析平台对陈皮主要化学成分及相关作用靶点进行收集。从GeneCards数据库中检索理气、代谢相关脂肪性肝病相关靶点，对理气靶点、代谢相关脂肪性肝病靶点与药效靶点进行映射，得出陈皮理气功效治疗非酒精性脂肪肝的功效靶点。将功效靶点输入STRING数据库中得出蛋白相互作用（PPI）网络，并用Cytoscape 3.9.0软件进行可视化。通过DAVID数据库进行基因本体（GO）与京都基因与基因组百科全书（KEGG）通路富集分析。筛选出陈皮关键活性化合物和靶基因后，进行分子对接，预测活性化合物与核心靶点的结合，得出其可能作用的分子机制并构建“化合物–靶点–通路”网络图。结果 陈皮中共有63种活性成分和540个相应靶点，理气靶点580个，代谢相关脂肪性肝病靶点478个。最终筛选获得56个关键靶点和16个重要的信号通路，包括磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B1（Akt）信号通路、Ras信号通路、胰岛素信号通路、腺苷酸活化蛋白激酶（AMPK）信号通路、核因子-κB（NF-κB）信号通路等。陈皮理气功效治疗代谢相关脂肪性肝病的主要成分为川陈皮素、柚皮素、橙皮苷等，关键靶点为Akt1、过氧化物酶体增殖物激活受体（PPAR）α、PPARγ、表皮生长因子受体（EGFR）等。分子对接显示柚皮素、川陈皮素、柚皮苷分别与Akt1、PPARγ、原癌基因c（JUN）、雌激素受体α（ESR1）、PPARα结合良好。结论 陈皮中的柚皮素、川陈皮素、柚皮苷可能为其发挥理气功效的主要活性成分，能够多靶点、多途径地调控氧化应激、炎症反应、脂质代谢等生物效应过程治疗非酒精性脂肪肝，为陈皮在临床上治疗非酒精性脂肪肝的深入研究提供理论基础和科学依据。

Objective To explore the key active ingredients and action targets and pathways of Citrus Reticulata in treatment of metabolic associated fatty liver disease through the effects of regulating qi by network pharmacology and molecular docking techniques, in order to investigate its possible pharmacological basis and potential molecular mechanisms. Methods The main chemical components and related targets of action of Citrus Reticulata were collected through the systematic pharmacology database and analytical platform of traditional Chinese medicine. The disease related targets related to regulate qi and metabolic associated fatty liver disease were retrieved from the GeneCards database, and the regulate qi targets, metabolic associated fatty liver disease targets and pharmacodynamic targets were mapped to derive the efficacy targets of the regulate qi effect of Citrus Reticulata for the treatment of metabolic associated fatty liver disease. The efficacy targets were entered into the STRING database to derive a PPI interaction network and visualized using Cytoscape 3.9.0 software. The GO and KEGG pathways were enriched by the DAVID database. After screening the key active compounds and target genes of Citrus Reticulata, molecular docking was carried out to predict the binding of the active compounds to the core targets, to identify the possible molecular mechanisms of action and to construct a “compound – target – pathway” network map. Results A total of 63 active ingredients and 540 corresponding targets were identified in Citrus Reticulata, 580 in regulating qi and 478 in metabolic associated fatty liver disease. 56 Key targets and 16 important signaling pathways were identified, such as PI3K/Akt signaling pathway, Ras signaling pathway, insulin signaling pathway, AMPK signaling pathway, NF-κB signaling pathway, etc. The main components of Citrus Reticulata's regulating qi efficacy in treating metabolic associated fatty liver disease are nobiletin, naringenin, and hesperidin C, and the key targets are Akt1, PPARα, PPARγ, and EGFR. In addition, molecular docking showed that nobiletin, naringenin and hesperidin bound well to Akt1, PPARγ, JUN, ESR1, and PPARα, respectively. Conclusion Naringenin, nobiletin, and naringenin in Citrus Reticulata may be the main active components for its rational qi effect, which can regulate the biological effect processes of oxidative stress, inflammatory response and lipid metabolism in treatment of metabolic associated fatty liver disease in a multi-target and multi-pathway manner, providing a theoretical basis and scientific basis for the in-depth study of Citrus Reticulata in treatment of metabolic associated fatty liver disease in clinical practice.

R285

国家自然科学基金资助项目（8217140778，8214100583）；广东省基础与应用基础研究基金项目（2021A1515011697）；2021年高校教师特色创新研究项目（2021SWYY05）