14-3-3η Induces a Multidrug-Resistant Phenotype in Rheumatoid Arthritis via p53 Dysregulation: Insights from AIA Models

Rheumatoid arthritis (RA) is a chronic autoimmune condition complicated by drug resistance issues, significantly challenging its treatment. The protein 14-3-3η has been noted for its association with drug resistance in various cancers, and while it is particularly expressed at high levels in RA patients, its role in the disease's pathogenesis is not well understood. This study explores how 14-3-3η contributes to drug resistance in RA, particularly focusing on its interactions with the p53 protein. Through techniques including qPCR, Western blot, ELISA, BLI, immunoprecipitation, and the use of adjuvant-induced arthritis (AIA) transgenic models, we observed elevated levels of 14-3-3η in the peripheral blood mononuclear cells (PBMCs) of RA patients, correlating with both disease activity and duration. Enhanced expression of 14-3-3η was found to induce resistance to methotrexate (MTX) in AIA rats, which could be countered by treatment with arsenic trioxide (ATO). Our mechanistic studies suggest that the overexpression of 14-3-3η promotes a multidrug resistance phenotype in rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) through the downregulation of p53. Furthermore, adenovirus-mediated p53 supplementation in AIA rats was able to mitigate and reverse the MTX resistance caused by 14-3-3η. These findings delineate a regulatory function for 14-3-3η in the pathogenesis and drug resistance of RA via p53 modulation, proposing it as a viable target for treating drug-resistant RA.