C15 is actionable drug target for anti-arthritis via activation Nrf2 signaling

Abstract SNM is a purified compound isolated from Chinese Medicinal plant. In the current study, we found that SNM not only ameliorated the progression of collagen induced arthritis (CIA), but protected joints from destruction in mice, indicating that SNM probably restricted the local inflammation of arthritic joints. As synovium in the joints is the major target tissue of rheumatoid arthritis, the synovium fibroblasts derived from RA patients (RASFs) were employed to validate the anti-arthritic effect and explore underlying mechanism of SNM. The results demonstrated that SNM significantly inhibited IL-6 and IL-33 secretion, COX-2 expression and ROS production in RASFs. Mass spectrometry results demonstrated that cysteine 26 (C26) and lysine 873 (K873) of C15 are a direct target of SNM. Underlying mechanistic study showed that knockdown C15 resulted in the accumulation and phosphorylation of p62 and aggregation of Nrf2 and HO-1 in cytoplasma of RASFs. Consistently, SNM activated p62/Nrf2 signaling in RASFs via covalently binding at C26 and K873 of C15. Furthermore, the collagen antibody-induced arthritis (CAIA) model was established in Nrf2−/− mice to verify the role of Nrf2 in the anti-arthritic effect of SNM, and the results explored that Nrf2−/− mice are resistant to the anti-arthritic effect of SNM. Our findings explored that C15 is an actionable drug target for anti-arthritis via activation Nrf2 signaling.