目的 通过滑膜液与血清代谢组学探究马钱子碱载药微针不同给药方式对胶原诱导性关节炎（collagen-induced arthritis，CIA）大鼠的代谢调节作用，为揭示马钱子碱载药微针治疗类风湿性关节炎（rheumatoid arthritis，RA）的药效机制提供实验依据。方法 采用超高液相色谱串联质谱（ultra-high performance liquid chromatography-tandem mass spectrometry，UPLC-MS/MS）非靶向代谢组学方法，将对照组、马钱子碱水凝胶穴位微针组（XWMN）、马钱子碱水凝胶非穴位微针组（FXWMN）、空白微针组（KBMN）及传统针刺组（ZC）分别与模型组比较，系统分析干预后CIA大鼠滑膜液与血清内源性代谢物谱变化。结果 基于滑膜液代谢组学筛选获得各给药组与模型组比较的差异代谢物，通过对差异代谢物的回调趋势分析发现，与模型组比较，XWMN组3种代谢物显著回调，FXWMN组5种代谢物显著回调，KBMN组3种代谢物显著回调，ZC组3种代谢物显著回调；XWMN组代谢调控主要涉及环磷酸腺苷（cyclic adenosine monophosphate，cAMP）信号通路、丁酸代谢、核苷酸代谢等通路，富集的通路数量多于其他给药组。基于血清代谢组学筛选获得各给药组与模型组比较的差异代谢物，通过对差异代谢物的回调趋势分析发现，与模型组比较，XWMN组5种代谢物显著回调，FXWMN组15种代谢物显著回调，KBMN组12种代谢物显著回调，ZC组3种代谢物显著回调；XWMN组代谢调控主要涉及嘌呤代谢、花生四烯酸代谢等RA关键致病通路，FXWMN组涉及嘌呤代谢、ABC转运器通路等3条通路，KBMN组涉及嘌呤代谢、亚油酸代谢等7条代谢通路。结论 马钱子碱载药微针不同给药方式均能不同程度调节CIA大鼠的异常代谢。其中，马钱子碱载药微针穴位给药可通过调控滑膜液中3-羟基丁酸、脱氧胞苷等代谢物表达，作用于cAMP信号通路、丁酸代谢、核苷酸代谢等通路，抑制炎症反应、调节免疫细胞分化，同时通过调控血清嘌呤代谢、花生四烯酸代谢通路，发挥抗炎作用。相较于非穴位给药、空白微针及传统针刺，穴位给药对关键致病通路（如嘌呤代谢、花生四烯酸代谢）的干预作用更为突出。

Objective To explore the metabolic regulatory effects of different administration methods of brucine-loaded microneedles on rats with collagen-induced arthritis (CIA) through synovial fluid and serum metabolomics, and to provide experimental evidence for elucidating the mechanism of brucine-loaded microneedles in the treatment of rheumatoid arthritis (RA).Methods The non-targeted metabolomics method of ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was adopted. The control group, brucine-loaded hydrogel acupoint microneedles group (XWMN), brucine-loaded hydrogel non-acupoint microneedles group (FXWMN), blank microneedles group (KBMN) and traditional acupuncture group (ZC) were respectively compared with model group. The changes in the profiles of endogenous metabolites in the synovial fluid and serum of CIA rats after intervention were systematically analyzed.Results Based on the screening of synovial fluid metabolomics, differential metabolites were obtained for comparison between each treatment group and the model group. Analysis of the reversal trends of the differential metabolites showed that, compared with model group, three metabolites in XWMN group, five in FXWMN group, three in KBMN group, and three in ZC group were significantly restored toward normal levels. The metabolic regulation of XWMN group mainly involved the cyclic adenosine monophosphate (cAMP) signaling pathway, butyrate metabolism, nucleotide metabolism and other pathways, with a higher number of enriched pathways compared to other treatment groups. Based on serum metabolomics screening, differential metabolites were obtained for comparison between each treatment group and the model group. Through the analysis of the regression trend of differential metabolites, it was found that compared with model group, five metabolites in XWMN group showed significant regression, 15 metabolites in FXWMN group showed significant regression, 12 metabolites in KBMN group showed significant regression, and three metabolites in ZC group showed significant regression; The metabolic regulation of XWMN group mainly involved key pathogenic pathways such as purine metabolism and arachidonic acid metabolism in RA, while FXWMN group involved three pathways including purine metabolism and ABC transporter pathway, and KBMN group involves seven metabolic pathways including purine metabolism and linoleic acid metabolism. Conclusion Different administration methods of brucine-loaded microneedles can modulate the aberrant metabolism in CIA rats to varying degrees. Notably, acupoint administration of brucine-loaded microneedles exerts anti-inflammatory effects and regulates immune cell differentiation by modulating the expression of metabolites such as 3-hydroxybutyrate and deoxycytidine in synovial fluid, thereby influencing pathways like cAMP signaling, butanoate metabolism, and nucleotide metabolism. Concurrently, it exerts anti-inflammatory effects by modulating serum metabolic pathways including purine metabolism and arachidonic acid metabolism. Compared with non-acupoint administration, blank-microneedle treatment and traditional acupuncture, acupoint administration demonstrates a more prominent modulatory effect on key pathogenic pathways (e.g., purine metabolism, arachidonic acid metabolism).

R285.5

国家自然科学基金资助项目（82260770）；贵州省高层次创新型人才（黔科合平台人才-GCC［2023］037）；贵州中医药大学国家与省级科技创新人才团队培育项目（贵中医TD合字［2022］004号）；贵州中医药大学药用高分子材料研究中心（贵中医党办发［2019］70）