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).

brucine  /  hydrogel microneedles  /  rheumatoid arthritis  /  synovial fluid  /  serum metabolomics  /  purine metabolism  /  arachidonic acid metabolism  /  cAMP signaling pathway