目的 通過網絡藥理學及分子對接技術挖掘陳皮通過理氣功效治療代謝相關脂肪性肝病的關鍵有效成分及作用靶點與通路，以探究其可能的藥效物質基礎及潛在的分子機制。方法 通過中藥系統(tǒng)藥理學數(shù)據(jù)庫和分析平臺對陳皮主要化學成分及相關作用靶點進行收集。從GeneCards數(shù)據(jù)庫中檢索理氣、代謝相關脂肪性肝病相關靶點，對理氣靶點、代謝相關脂肪性肝病靶點與藥效靶點進行映射，得出陳皮理氣功效治療非酒精性脂肪肝的功效靶點。將功效靶點輸入STRING數(shù)據(jù)庫中得出蛋白相互作用（PPI）網絡，并用Cytoscape 3.9.0軟件進行可視化。通過DAVID數(shù)據(jù)庫進行基因本體（GO）與京都基因與基因組百科全書（KEGG）通路富集分析。篩選出陳皮關鍵活性化合物和靶基因后，進行分子對接，預測活性化合物與核心靶點的結合，得出其可能作用的分子機制并構建“化合物–靶點–通路”網絡圖。結果 陳皮中共有63種活性成分和540個相應靶點，理氣靶點580個，代謝相關脂肪性肝病靶點478個。最終篩選獲得56個關鍵靶點和16個重要的信號通路，包括磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B1（Akt）信號通路、Ras信號通路、胰島素信號通路、腺苷酸活化蛋白激酶（AMPK）信號通路、核因子-κB（NF-κB）信號通路等。陳皮理氣功效治療代謝相關脂肪性肝病的主要成分為川陳皮素、柚皮素、橙皮苷等，關鍵靶點為Akt1、過氧化物酶體增殖物激活受體（PPAR）α、PPARγ、表皮生長因子受體（EGFR）等。分子對接顯示柚皮素、川陳皮素、柚皮苷分別與Akt1、PPARγ、原癌基因c（JUN）、雌激素受體α（ESR1）、PPARα結合良好。結論 陳皮中的柚皮素、川陳皮素、柚皮苷可能為其發(fā)揮理氣功效的主要活性成分，能夠多靶點、多途徑地調控氧化應激、炎癥反應、脂質代謝等生物效應過程治療非酒精性脂肪肝，為陳皮在臨床上治療非酒精性脂肪肝的深入研究提供理論基礎和科學依據(jù)。

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

國家自然科學基金資助項目（8217140778，8214100583）；廣東省基礎與應用基礎研究基金項目（2021A1515011697）；2021年高校教師特色創(chuàng)新研究項目（2021SWYY05）