Aqueous extract of Saposhnikovia divaricata root alleviates rheumatoid arthritis by acting on TNF-α and RAGE signaling pathways.

Saposhnikovia divaricata (Turcz.) Schisch (SADS) is classified as a special-grade traditional Chinese medicine in Shennong's Materia Medical due to its immune-protective effects, including dispelling cold, relieving edema and pain, and its potential in treating rheumatoid arthritis (RA). Over 130 traditional Chinese medicine formulations containing SADS are used for RA treatment. However, the active ingredients and serum metabolites of SADS remain underexplored, and its precise mechanism of action in RA is not fully understood. Therefore, the study aims to explore the active ingredients and serum metabolites of SADS by UPLC-Q-TOF-MS and investigate its therapeutic mechanisms in the context of RA. A total of 5536 compounds were identified in SADS, and 19 active components were finally selected. In serum metabolites following SADS administration, 4945 compounds were identified, of which 17 showed anti-inflammatory activity. Network pharmacology analysis showed that SADS may play a role in the treatment of RA through the TNF and Receptor for Advanced Glycation End-products (RAGE) signaling pathway. SADS alleviated RA symptoms in IL-1RA deficient RA mice. In cellular models, SADS inhibited the abnormal proliferation of fibroblast-like synoviocytes through regulating the TNF-α and RAGE pathways. In addition, SADS promoted the polarization of M2 macrophages but inhibited the polarization of M1 macrophages. SADS alleviated the progression of experimental arthritis in a RA mouse model by modulating the TNF-α and RAGE signaling pathways, supporting its potential as a therapeutic agent for RA.