Qufeng epimedium decoction alleviates rheumatoid arthritis through CYLD-antagonized NF-kB activation by deubiquitinating Sirt1

Background

Rheumatoid arthritis (RA) is a chronic autoimmune disease that markedly limits the patients´ day-to-day functional abilities and life quality. Currently, there is no known cure for RA. Qufeng epimedium decoction, a traditional Chinese medicine, is widely used in China to treat RA. However, its underlying mechanism remains elusive.

Methods

The RA animal model was established to investigate the anti-RA effect and regulatory effect on fibroblast-like synoviocytes (FLS) pyroptosis, qRT-PCR, Western blot, flow cytometry, histology staining, and ELISA were utilized to confirm the gene and protein expressions. The interactions between Sirt1 and CYLD were validated through Co-immunoprecipitation (Co-IP) and RNA-FISH assay.

Results

Administration with Qufeng epimedium decoction attenuated inflammatory damage, excessive proliferation, and FLSs pyroptosis in an RA rat model. Moreover, treatment of Qufeng epimedium decoction reduced the ubiquitination modification level of Sirt1 in FLSs isolated from an RA rat model. Mechanistically, CYLD, an intermediation for linking Qufeng epimedium decoction and RA, was responsible for Sirt1 deubiquitination to its protein stabilization, thereby deactivating the NF-kB /GSDMD signaling pathway.

Conclusion

Our findings indicate that Qufeng epimedium decoction suppresses FLSs pyroptosis and RA progression via CYLD-mediated Sirt1 deubiquitination and deactivation of the NF-kB /GSDMD signaling pathway. This study sheds light on the underlying mechanism of Qufeng epimedium decoction's effectiveness in RA treatment.