Rutaceae Zanthoxylum–Derived 7-Demethylsuberosin Alleviates the Rheumatoid Arthritis Through Inhibiting the Maturation of Dendritic Cells via Targeting MAPK14 Functional Food-Based 7-Demethylsuberosin

Zanthoxylum ailanthoides , a medicinal and edible plant, was mostly used as medicinal materials or spices, in which 7-demethylsuberosin (7-Dem) was identified as active component, but its function and mechanism on dendritic cells (DCs) are not clear. The objective of this study was to explore the effect and mechanism of 7-Dem on the maturation and function of DCs in the treatment of rheumatoid arthritis. The impact of 7-Dem on DCs was assessed using flow cytometry and ELISA. Agonists of the Toll-like receptor pathway and cytochalasin D were employed to validate the pathway affected by 7-Dem. Furthermore, molecular docking, network pharmacology, Western blotting, and CETSA were used to explore the targets of 7-Dem. The immunomodulatory effects of 7-Dem were examined using the adjuvant-induced arthritis (AIA) mouse model. The results showed that 7-Dem did not damage the viability of DCs at doses below 10 µM but suppressed the maturation of DCs induced by lipopolysaccharide in vitro and in vivo , enhanced phagocytosis, and restrained migration. DCs exhibited an impaired stimulation of CD4 + T cell proliferation and restored the imbalance of CD4 + T cell subtypes after treatment with 7-Dem. At molecular levels, 7-Dem inhibited the maturation of DCs induced by agonists and decreased the expression of TRAF6, not TRAF3. Furthermore, 7-Dem improved the thermal stability and reduced the phosphorylation of MAPK14. In vivo , 7-Dem alleviated joint inflammation with restored imbalance of T cell subtypes. In conclusion, 7-Dem inhibits the maturation and function of DCs by targeting MAPK14 and inhibiting the phosphorylation of MAPK14, which thereby restores immune tolerance and alleviates inflammation in the AIA joints.