Exploring the alleviating effect and mechanism of the diterpenoid alkaloid Polyschistine D on rheumatoid arthritis based on network pharmacology and non-targeted metabolomics.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. The pathogenesis is complex, and the pathological manifestations are mainly articular cartilage and bone injury, synovial destruction, pannus hyperplasia and inflammatory cell infiltration. Polyschistine D (PD) is a natural active product derived from the Chinese herbal medicine Aconitum pendulum Busch. In traditional Chinese medicine, it is employed to treat rheumatism, fever and pain. However, the precise mechanism by which it treats rheumatoid arthritis (RA) remains to be elucidated. The purpose of this research was to investigate the effect of PD intervention on joint inflammation associated with RA and to elucidate its underlying mechanisms of action. Network pharmacology and non-targeted metabolomics analysis were employed to elucidate the potential mechanism of PD in the treatment of RA. The RA model in DBA/1 mice was induced using bovine type II collagen. Following PD gavage, the clinical arthritis index was assessed, and pathological changes in the ankle joint were examined. Enzyme-linked immunosorbent assay (ELISA), RT-qPCR, and western blotting (WB) were performed to further clarify the mechanism of PD in RA treatment. To the best of our knowledge, the present work was the first to demonstrate the anti-RA effect of PD, showing its ability to reduce cartilage degradation and bone erosion. We also provide evidence that the therapeutic action of PD may involve the inhibition of the JAK/STAT and PI3K/Akt/mTOR pathway, which help alleviate joint inflammation, reduce articular cartilage degradation, and downregulate the expression of MMP2 and MMP9 proteins.