ATP2A3 promotes inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes via activation of the STING signaling pathway

Background Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial inflammation and progressive bone destruction. Endoplasmic reticulum (ER) stress plays a key role in the pathogenesis of RA. However, the biomarkers of ER stress in RA remain elusive. We aimed to identify key ER stress-related genes (ERSRGs) in RA, evaluate their diagnostic potential, and investigate their functional roles. Methods. Transcriptomic data from six RA datasets were analyzed using machine learning algorithms. ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2 + Transporting 3 (ATP2A3) expression was validated via immunohistochemistry (IHC). Cytokine secretion and signaling pathways in RA fibroblast-like synoviocytes (FLS) were examined using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. Results Seventeen ERSRGs were identified by intersecting differentially expressed genes (DEGs) between RA and control samples with ERSRGs from the Gene Ontology Consortium. RA patients were classified into two molecular subtypes based on the expression pattern of these 17 genes. Using machine learning, ATP2A3 emerged as key diagnostic biomarker in RA and was validated in external datasets. IHC further confirmed ATP2A3 was highly expressed in RA synovial tissues. Importantly, we found that ATP2A3 promotes the secretion of inflammatory cytokines in RA FLS. Mechanistically, ATP2A3 enhances the phosphorylation of stimulator of interferon genes (STING), thereby activating the STING signaling pathway and leading to increased inflammatory cytokine secretion. Conclusions We establish ATP2A3 as a promising diagnostic biomarker for ER stress in RA and demonstrate that it promotes the secretion of inflammatory cytokines in RA FLS through STING pathway activation.