Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation and joint bone destruction. Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of autoimmune diseases such as RA, yet the specific mechanism through which ER stress contributes to RA remains unclear. This study aims to investigate the role and mechanism of ER stress-related genes in promoting RA, with the goal of identifying novel therapeutic targets.

Methods: Transcriptomic data from six RA datasets were analyzed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) to identify ER stress-related genes (ERSRGs). Protein-level validation was conducted via Immunohistochemistry (IHC) on RA synovial tissues and control synovial tissues.The expression levels of ATP2A3, STING, TBK1, IRF3, and NF-κB in fibroblast-like synoviocytes (FLS) were detected by Western blot (WB).Cell invasion and migration abilities were assessed using Transwell assays. The levels of inflammatory cytokines IL-6, IL-1β, TNF-α, and IFN-γ were measured by ELISA.

Results: Seventeen ERSRGs were identified by intersecting differentially expressed genes (DEGs; n=1433) between RA and control samples with ERSRGs (n=267) from the Gene Ontology Consortium.Among the differentially expressed genes, ATP2A3—an ER stress-induced gene—was found to be significantly upregulated in RA. Overexpression of ATP2A3 in FLS promoted cell migration, invasion, and the release of inflammatory cytokines including IL-6, IL-1β, TNF-α, and IFN-γ. Furthermore, ATP2A3 facilitated the phosphorylation of STING, thereby activating the STING signaling pathway, which enhanced FLS invasion, migration, and inflammatory cytokine secretion.

Conclusion: This study demonstrates that the ER stress-induced gene ATP2A3 plays a crucial role in RA pathogenesis. ATP2A3 promotes the development and progression of RA by activating the STING signaling pathway. These findings highlight ATP2A3 as a potential therapeutic target for the treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/er-stress-induced-atp2a3-drives-rheumatoid-arthritis-via-activation-of-sting-signaling/