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

ABSTRACT 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.