目的 通过网络药理学、分子对接及动物实验探讨沙棘对肝脏脂质蓄积的作用机制。方法 中药系统药理学数据库与分析平台（TCMSP）、Swiss Target Prediction数据库筛选沙棘的活性成分和靶点，Gene Cards及OMIM数据库获取代谢相关脂肪性肝病（MAFLD）相关疾病靶点，Cytoscape构建“药物-成分-靶点”网络。蛋白质-蛋白质相互作用（PPI）网络分析识别关键靶点，对核心靶点进行基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析，将主要成分和靶点进行分子对接。24只ApoE^-/-小鼠分为对照组、模型组和沙棘低、高剂量（100、200 mg·kg^-1）组。对照组饲喂普通饲料，其他组饲喂高脂饲料16周，沙棘组ig给药16周。检测小鼠血脂水平，苏木精-伊红（HE）染色检测肝脏病理形态，油红O染色检测肝脏脂质蓄积，测定肝脏脂质总胆固醇（TC）、三酰甘油（TG）水平，蛋白质印迹法（Western blotting）检测过氧化物酶体增殖物激活受体γ（PPARγ）、沉默调节蛋白1（SIRT1）、磷脂酰肌醇3-激酶/蛋白激酶B（PI3K-Akt）相关蛋白表达。结果 筛选沙棘活性成分33种，作用靶点345个，MAFLD相关靶点1 832个，共同靶点120个，核心靶点为雌激素受体1（ESR1）、丝氨酸/苏氨酸蛋白激酶1（Akt1）、PPARG、SIRT1等，主要通过调控PI3K-Akt信号通路等，分子对接表明主要成分与关键靶点结合活性良好。动物实验结果表明，沙棘可降低TC、TG及低密度脂蛋白胆固醇（LDL-C）水平，升高高密度脂蛋白胆固醇（HDL-C）水平，减少肝脏脂肪变性及脂质蓄积，降低肝脏TC、TG水平，升高PPARγ、SIRT1及p-PI3K、p-Akt蛋白表达。结论 沙棘调节血脂，减少肝脏脂质蓄积，其机制可能与激活PPARγ/SIRT1和PI3K/Akt信号通路相关。

Objective To explore the mechanism of Hippophae Fructus on metabolic dysfunction-associated fatty liver disease (MAFLD) through network pharmacology, molecular docking and animal experiments. Methods The active components and targets of Hippophae Fructus were screened by TCMSPS and Swiss Target Prediction databases, and the disease targets related to MAFLD were obtained from Gene Cards and OMIM databases. The "drug-component-target" network was constructed by Cytoscape. The key targets were identified by PPI network analysis, and GO and KEGG pathway enrichment analysis were performed on the core targets. Molecular docking was conducted on the main components and targets. Total of 24 ApoE^-/- mice were divided into control group, model group, low- and high-dose (100 and 200 mg·kg^-1) Hippophae Fructus group. The control group was fed with normal diet, and the other groups were fed with high-fat diet for 16 weeks. The Hippophae Fructus groups were given intragastric administration for 16 weeks. The blood lipid levels of mice were detected, and the liver pathological morphology was detected by HE staining. The liver lipid accumulation was detected by Oil Red O staining, and the levels of TC and TG in the liver were determined. The expressions of PPARγ, SIRT1, and PI3K/AKT-related proteins were detected by Western blotting. Results A total of 33 active components and 345 targets of Hippophae Fructus were screened, 1 832 MAFLD-related targets were obtained, and 120 common targets were identified. The core targets were ESR1, AKT1, PPARG, SIRT1, etc. The main mechanism was through the PI3K-Akt signaling pathway, and the molecular docking showed that the main components had good binding activity with the key targets. The animal experiment results showed that Hippophae Fructus reduced serum TC, TG and LDL-C levels (P < 0.01), increased HDL-C levels (P < 0.05), reduced liver steatosis and lipid accumulation, decreased liver TC and TG levels (P < 0.05, 0.01), increased PPARγ, SIRT1, p-PI3K and p-Akt protein expression (P < 0.01). Conclusion Hippophae Fructus reduces blood lipids and liver lipid accumulation, and its mechanism may be related to the activation of PPARγ/SIRT1 and PI3K/AKT signaling pathway.

R285.5

国家自然科学基金项目（82374077）；陕西省中医药科研创新人才项目（TZKN-CXRC-02）；咸阳市科技创新人才项目（L2024-CXNL-KJRCTD-KJRC-0003）；秦创原中医药产业创新聚集区项目（L2024-QCY-ZYYJJQ-X45）；大学生创新创业训练计划项目（202310716075）