Single-cell multi-dimensional data analysis decodes RNF19A-mediated drug resistance in rheumatoid arthritis fibroblast-like synoviocytes: mechanisms and biological insights

Rheumatoid arthritis (RA) is a prevalent autoimmune disease, affecting approximately 1% of the global population. Methotrexate (MTX) is the most widely prescribed drug for RA treatment; however, its efficacy is often limited, with resistance frequently observed. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA progression and are closely linked to drug resistance, although the underlying mechanisms remain poorly understood. In this study, we conducted a comprehensive analysis of public single-cell transcriptomics data from osteoarthritis and rheumatoid arthritis synovial tissues, identifying RNF19A as a gene potentially associated with RA resistance in FLS. Our findings indicate that RNF19A is significantly overexpressed in drug-resistant FLS and is closely associated with the dysregulation of FLS proliferation, migration, invasion, and apoptosis. Furthermore, we demonstrated that RNF19A promotes functional disruption in FLS by ubiquitinating and degrading MKP-1, thereby activating the MAPK signaling pathway. This activation also facilitates the nuclear translocation of ZBTB20, an upstream transcription factor of RNF19A, which further enhances RNF19A transcription. This biological process creates a positive feedback loop in FLS, contributing to RA resistance-a mechanism that was also validated in vivo. In summary, this study is the first to underscore the crucial role of RNF19A in mediating drug resistance in RA FLS, elucidating the underlying biological processes, and providing novel insights into RA pathogenesis, thereby offering a new experimental foundation for RA drug development.