Proteomic and network pharmacology analyses reveal S100A8 as the anti-inflammatory target of Yunpi Jiedu Tongluo Qushi Granule in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation. RA has a global prevalence between 0.5 % and 1 % although its pathogenesis is not completely understood. Chinese herbal medicine such as Yunpi Jiedu Tongluo Qushi Granule (YJTQG) is one of the treatments for RA. However, the underlying mechanism of action is unclear. Here, analysis of clinical samples reveals that YJTQG can reduce the inflammatory factors and alleviate the symptoms of RA patients. Quantitative proteomic analysis of serum proteomes of RA patients identifies the potential therapeutic targets of YJTQG. We use biochemical experiments to validate several differentially expressed proteins, discover S100A8 as a possible therapeutic target of YJTQG, and analyze the correlation between S100A8 and several known RA biomarkers. Network pharmacology analysis discloses COX1/2 and NOS2 as potential targets of key compounds in YJTQG and protein-protein interaction network analysis reveals TNFα, IL-6, and STAT3 as possible core targets of YJTQG. Bioinformatic and patient sample analyses indicate that YJTQG may reduce S100A8 expression by suppressing its transcription. Mechanistically, we find that kaempferol and quercetin in YJTQG may reduce the expression of S100A8 by inhibiting the phosphorylation, nuclear translocation, and transcriptional activity of p65 in the lipopolysaccharide-stimulated RAW264.7 cells. Therefore, our work demonstrates that S100A8 is a potential therapeutic target of YJTQG for RA, which may provide a new direction for developing new treatments for RA patients.