目的 通过网络药理学以及动物实验探讨六棱菊对代谢相关脂肪性肝病（MAFLD）模型小鼠的干预作用及潜在的分子机制。方法 通过文献检索得到六棱菊的活性成分，通过SwissTargetPredicton和疾病数据库（GeneCards）和PharmMapper数据库预测六棱菊成分相关靶标，Genecards数据库获取MAFLD和氧化应激相关靶标，通过STRING和Cytoscape3.9.1软件建立蛋白质-蛋白质相互作用（PPI）网络模型并找到关键靶点。对六棱菊治疗MAFLD的靶标进行GO富集分析与KEGG通路富集分析。将50只C57BL/6J雄性无菌小鼠适应性饲养1周后随机分为5组，分别为对照组、模型组及六棱菊提取物低、中、高剂量（1.25、2.50、5.00 g·kg^-1）组；小鼠给予高脂饲料8周进行MAFLD造模，造模后给药6周。实验第14周末处死小鼠，比较各组小鼠肝脏指数、肝组织病理变化，测定各组小鼠血清中炎症因子的水平及肝脏中脂肪含量，测定血清转氨酶、肝脏脂肪水平以及肝组织的氧化损伤指标丙二醛（MDA）、还原型谷胱甘肽（GSH）、超氧化物歧化酶（SOD）水平，检测核因子E₂相关因子2 （Nrf2）信号通路重要基因和蛋白Nrf2、NAD（P）H喹啉氧化酶1 （Nqo1）、糖原合成酶激酶-3β （GSK-3β）和非受体酪氨酸蛋白激酶（Fyn）的表达水平。结果 网络药理学获得六棱菊、MAFLD、氧化应激的交集靶点共304个，六棱菊可能通过TNF、AKT1、ALB、EGFR、STAT3、NFE₂L2等核心靶点作用于HIF-1、糖尿病并发症中的AGE-RAGE、甲状腺激素、FoxO、PI3K-Akt、TNF信号通路等发挥MAFLD治疗作用。动物实验结果显示，与对照组比较，模型组小鼠的整体状态差，肝脏组织大面积脂肪变性及脂质浸润，血清转氨酶、肝脏脂肪水平明显升高，证实了高脂饲料饮食喂养8周成功构建了小鼠MAFLD模型；各药物干预治疗组小鼠肝脏指数、肝脏病理变化和肝脏脂肪水平，血清转氨酶、脂质过氧化水平和Nrf2信号通路重要基因和蛋白表达均较模型组显著改变（P＜0.05），其中，六棱菊提取物高剂量组改变最为明显。结论 不同剂量六棱菊提取物干预均能明显改善MAFLD小鼠血清中炎症因子水平，肝脏脂质沉积、肝功能指标，降低肝脏指数，可能与调控Nrf2信号通路的表达，降低肝组织中脂质过氧化水平和炎症反应的表达有关。

Objective To investigate the effect and potential molecular mechanism of Laggera alata extract on alleviates metabolismrelated fatty liver disease (MAFLD) through network pharmacology and drug intervention. Methods The active ingredients of Laggera alata extract were analyzed through literature retrieval and the elated targets were predicted by SwissTargetPredicton and Pharm Mapper databases. MAFLD and oxidative stress-related targets were obtained by Genecards database. PPI network model was established and key targets were found by STRING and Cytoscape 3.9.1 software. Besides, GO enrichment analysis and KEGG pathway enrichment analysis were performed on the targets of hexagon chrysanthemum in the treatment of MAFLD. 50 male sterile C57BL/6J mice were randomly divided into five groups after one week of adaptive feeding, which were control group, model group, low dose group, medium dose group and high dose group of Laggera alata extract. The experimental mice were given high-fat diet for MAFLD modeling, and the low, medium and high dose groups (1.25, 2.50, and 5.00 g·kg^-1) were given daily by gavage. Mice in each intervention treatment group were given ig administration once a day for six weeks. The mice were killed at the end of the 14th week of the experiment, and the liver index, liver tissue pathological changes, serum inflammatory factors and liver fat content, serum aminotransferase, liver fat level, oxidative damage index of liver malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD) levels and important genes and proteins of Nrf2 signaling pathway of the five groups of mice were compared. Expression levels of nuclear factor E₂ associated factor 2 (Nrf2), NAD(P)H quinoline oxidase 1 (Nqo1), glycogen synthase kinase-3β (GSK-3β) and non-receptor tyrosine protein kinase (Fyn). Results A total of 304 intersection targets of Laggera alata, MAFLD and oxidative stress were obtained by network pharmacology. Laggera alata may act on HIF-1, AGE-RAGE, thyroid hormone, FoxO, PI3K-Akt and TNF signaling pathways in diabetic complications through core targets such as TNF, AKT1, ALB, EGFR, STAT3 and NFE₂L2 to exert the therapeutic effect of MAFLD. Compared with the control group, the overall state of mice was poor, the liver tissues were large steatosis and lipid infiltration, and the serum aminotransferase and liver fat levels were significantly increased, which confirmed that the MAFLD model of mice was successfully constructed after eight weeks of high-fat diet. Liver index, liver pathological changes, liver fat level, serum aminotransferase, lipid peroxidation level and Nrf2 signaling pathway important gene and protein expression of mice in all drug intervention groups were significantly changed compared with model group, among which the changes were most obvious in high-dose group, and the results were statistically significant (P < 0.05). Conclusion Different doses of Laggera alata extract can significantly improve the levels of serum inflammatory factors, liver lipid deposition, liver function, and decrease liver index in MAFLD mice, which may be related to regulating the expression of Nrf2 signaling pathway, reducing the level of lipid peroxidation and the expression of inflammation in liver tissues.

R285.5

广西自然科学基金青年基金项目（2024GXNSFBA010302）;广西重点研发计划项目（桂科AB21196057）;国家中医药管理局高水平中医药重点学科建设项目-少数民族药学（壮药学）［zyyzdxk-2023165］;广西国际壮医医院”青苗工程“人才培育项目（编号：2022001）;广西国际壮医医院培育项目（2023GZYJKT008）;广西中医药多学科交叉创新团队项目（GZKJ2309）;广西中医药大学“高层次人才培育创新团队”项目（2022A008）;广西国际壮医医院2023年高层次人才队伍建设三年行动计划项目（GZCX20231203）;广西中医药大学第三批“岐黄工程”高层次人才团队培育项目（202414）