宣痹汤调节 NLRP3/Caspase-1/GSDMD/IL-1β 信号通路治疗急性痛风性关节炎的机制OA

Objective To screen the active components and therapeutic targets of Xuanbi Decoction(XBD)in the treatment of acute gouty arthritis(AGA)and to validate its molecular mechanism via the NLRP3/Caspase-1/GSDMD/IL-1β signaling pathway through animal experiments.Methods The active components and potential targets of XBD were screened using databases including TCMSP and Swiss Target Prediction.AGA-related targets were obtained from CTD,GeneCards,and other disease databases.A"drug-disease"intersection target protein-protein interaction(PPI)network was constructed.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed to predict core pathways.Molecular docking was conducted using AutoDock Vina to assess the binding affinity between key components and targets.A rat model of AGA induced by monosodium urate(MSU)crystals was established.Therapeutic effects of XBD were evaluated by measuring ankle swelling,serum levels of IL-1β and NLRP3,synovial histopathology,as well as the mRNA and protein expression levels of NLRP3,Caspase-1,GSDMD,and IL-1β.Results Network pharmacology identified 488 targets of XBD and 165"drug-disease"intersecting targets,which were enriched in the IL-17,TNF,and NLRP3 inflammasome pathways.Molecular docking showed that the top six active components of XBD exhibited high binding affinity to IL-1β and Caspase-3.In animal experiments,the high-,medium-,and low-dose XBD groups as well as the colchicine group significantly inhibited ankle swelling(P＜0.01),reduced serum IL-1β and NLRP3 levels(P＜0.01),and downregulated the mRNA expression of NLRP3,Caspase-1,GSDMD and IL-1β,as well as the protein expression of NLRP3,Caspase-1,GSDMD,IL-1β and PICK1 in synovial tissue(P＜0.01).Conclusion XBD alleviates acute gouty arthritis by inhibiting NLRP3 inflammasome activation and IL-1β release,and its mechanism may involve the mitigation of pyroptosis and oxidative stress.