目的 运用代谢组学联合网络药理学，系统解析桑寄生对类风湿关节炎大鼠的祛风湿效应及分子调控网络。方法 基于胶原诱导复合“风寒湿”刺激构建病证结合大鼠模型，桑寄生水提物（TCAE，28.35 g·kg^-1） ig干预27 d，观测足跖肿胀度、关节炎指数及免疫脏器指数；酶联免疫吸附试验（ELISA）法检测血清白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α表达水平。采用液相色谱-串联质谱（LC-MS/MS）非靶向代谢组学技术分析血清代谢轮廓，筛选差异代谢物并富集代谢通路；依托网络药理学平台预测桑寄生主要活性成分、潜在作用靶点及信号通路，经分子对接验证核心配体与关键受体的结合模式；最后将代谢组与网络药理数据进行联合通路整合分析。结果 与模型组比较，TCAE组大鼠足跖肿胀度、关节炎指数及脾脏、胸腺指数均显著下降（P＜0.01），血清IL-1β、TNF-α水平亦显著降低（P＜0.05、0.01）。代谢组学共检出5种桑寄生干预后显著回调的内源性差异代谢物（苏氨酸、苯乙醛、2-甲酰氨基苯甲酸、胸腺嘧啶、甲状腺素），主要映射至苯丙氨酸代谢、嘧啶代谢及色氨酸代谢等途径。网络药理学筛选出槲皮素、谷甾醇、番石榴苷、齐墩果酸4种核心成分，对应蛋白激酶B（Akt） 1、TNF、IL1B等94个RA相关靶点，显著富集于磷脂酰肌醇3-激酶（PI3K）-Akt信号通路、TNF信号通路、晚期糖基化终产物及其受体（AGE-RAGE）信号通路、IL-17信号通路、缺氧诱导因子-1（HIF-1）等信号通路；分子对接显示核心成分与关键靶蛋白的结合自由能均低于-20.92 kJ·mol^-1，提示结合活性良好。联合分析表明，花生四烯酸代谢与色氨酸代谢是两组学数据共关联的核心代谢枢纽。结论 桑寄生对风湿寒痹病证大鼠具有确切的抗炎及免疫调节作用，其机制可能与槲皮素、谷甾醇等活性成分靶向Akt1、TNF、IL1B等关键节点，协同干预花生四烯酸及色氨酸代谢通路，进而阻断炎症级联反应有关。

Objective To systematically elucidate the anti-rheumatic effect and molecular regulatory network of Taxillus chinensis in rats with wind-cold-dampness arthralgia syndrome by integrating metabolomics and network pharmacology. Methods A rat model of Wind-Cold-Dampness Arthralgia syndrome was established by collagen induction combined with “Wind-Cold-Dampness” environmental stimulation. Rats in the treatment group received aqueous extract of aqueous extract from Taxillus chinensis (TCAE, 28.35 g·kg^-1) by gavage for 27 consecutive days. Paw swelling, arthritis index, and spleen/thymus coefficients were measured; serum levels of IL^-1β and TNF-α were detected by ELISA. Non-targeted metabolomics based on LC-MS/MS was employed to profile serum metabolites, identify differential metabolites, and enrich metabolic pathways. Network pharmacology was applied to predict the main active components, potential targets, and signaling pathways of Taxillus chinensis, followed by molecular docking to verify the binding modes between core ligands and key receptors. Finally, joint pathway analysis of metabolomic and network pharmacological data was performed. Results Compared with the model group, TCAE exhibited markedly decreased paw swelling, arthritis index, and spleen/thymus coefficients (P<0.01), along with significantly reduced serum IL^-1β and TNF-α levels (P<0.05, 0.01). Metabolomics detected a total of five endogenous differential metabolites that were significantly reversed after TCAE (threonine, phenylacetaldehyde, 2-formamidobenzoic acid, thymine, thyroxine), which were primarily mapped to phenylalanine metabolism, pyrimidine metabolism, and tryptophan metabolism. Network pharmacology screened out four core components (quercetin, sitosterol, guavinoside A, oleanolic acid) corresponding to 94 RA-related targets including Akt1, TNF, and IL1B, which were significantly enriched in PI3K-Akt, TNF, and AGE-RAGE signaling pathways. Molecular docking showed that the binding free energies between core components and key target proteins were all below -20.92 kJ·mol-1, indicating favorable binding affinity. Joint pathway analysis revealed that arachidonic acid metabolism and tryptophan metabolism were the common core metabolic hubs co-associated by both omics datasets. Conclusion Taxillus chinensis exerts definite anti-inflammatory and immunomodulatory effects in rats with Wind-Cold-Dampness Arthralgia syndrome. The underlying mechanism may involve active components such as quercetin and sitosterol targeting key nodes including Akt1, TNF, and IL1B, synergistically regulating arachidonic acid and tryptophan metabolic pathways, thereby blocking the inflammatory cascade.

R965

广西自然科学基金项目（青年科学基金项目2023GXNSFBA026280）；广西“赋能”行动计划（广西重点研发项目）（桂科FN2600640125） ；广西中医药大学赛恩斯新医药学院校级科研项目（2025MS010）