To elucidate the active ingredients and potential mechanism of Solanum lyratum in the treatment of rheumatoid arthritis (RA), we employed a comprehensive strategy that combined network pharmacology and molecular docking. First, we systematically retrieved relevant compounds from S. lyratum documented in the literature. We obtained RA-related targets by querying GeneCards, DisGeNET, and the OMIM database. Subsequently, we constructed drug-compound-target and protein-protein interaction (PPI) networks to predict the promising protein targets of S. lyratum and identify the primary interactions between these protein targets and compounds. To validate our predicted candidate targets, we employed docking techniques. Finally, we conducted an in vitro intervention and validation using the ethyl acetate extract of S. lyratum on human RA synovial fibroblasts (MH7A). Our analysis identified a total of 41 potential active compounds and 126 intersecting pharmacological targets. GO enrichment analysis revealed that positive regulation of gene expression, response to hypoxia, and apoptotic processes were closely associated with S. lyratum treatment in RA. KEGG pathway analysis suggested that the TNF signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and Toll-Like receptor signaling pathway might play a pivotal role in S. lyratum intervention in RA. Consequently, key targets could include AKT1, TP53, VEGF, CASP3, TNF, and IL6. Molecular docking analysis indicated that diosgenin, strychnine, solamargine, solamarine, solasodine, and ursolic acid exhibited strong binding affinities with STAT3, JUN, MAPK1, TNF, TP53, IL6, MAPK8, IL1B, MMP1, and MMP3. These active compounds in S. lyratum had the potential to regulate multiple signaling pathways and target molecules, thereby exerting preventive and therapeutic effects in RA. In our in vitro experiment, we observed that the ethyl acetate extract of S. lyratum inhibited the proliferation of MH7A cells and reduced the release of cytokines. These experimental results aligned with the predictions generated through the network pharmacology approach. This study not only provided a theoretical foundation for the use of S. lyratum in the treatment of RA but also offered valuable insights for further investigations into the action mechanisms of Chinese herbal extract compounds.
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