Investigation On Network Targets Prediction And Pharmacological Mechanisms Of Guizhi-Shaoyao-Zhimu Decoction For Treatment Of Rheumatoid Arthritis

Guizhi-Shaoyao-Zhimu Decoction (GSZD) has been extensively used for rheumatoid arthritis (RA) therapy. However, its pharmacological mechanisms remain unclear due to a lack of appropriate scientific methodology. Here, we investigated GSZD’s mechanisms of action using an integrative approach that combined drug target prediction, network analysis, and experimental validation. As a result,77 putative targets were identified for 165 assessed chemical components of GSZD. After calculating the topological features of the nodes and edges in the created drug-target network, we identified a candidate GSZD-targeted signal axis that contained interactions between two putative GSZD targets [histone deacetylase 1 (HDAC1) and heat shock protein 90kDa alpha, class A member 1 (HSP90AA1)] and three known RA-related targets [NFKB2; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB); and tumor necrosis factor-alpha (TNF-a)]. This signal axis could connect different functional modules that are significantly associated with various RA-related signaling pathways, including T/B-cell receptor, Toll-like receptor, NF-kappa B and TNF pathways, as well as osteoclast differentiation. Furthermore, the therapeutic effects and putative molecular mechanisms of GSZD’s actions on RA were experimentally validated in vitro and in vivo. Collectively, GSZD may partially attenuate RA by reversing inflammation-immune system imbalance and regulating the HDAC1-HSP90AA1-NFKB2-IKBKB-TNF-a signaling axis.