Endoplasmic Reticulum Stress as a Stage-Dependent Regulatory Hub in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Beyond its canonical role in maintaining proteostasis, growing evidence indicates that endoplasmic reticulum (ER) stress acts as a dynamic regulatory hub integrating inflammatory signaling, metabolic reprogramming, and cell fate control within the RA synovium. Activation of the unfolded protein response (UPR) sensors-IRE1α, PERK, and ATF6-initially promotes adaptive compensation aimed at restoring ER homeostasis. However, sustained or maladaptive signaling drives inflammatory amplification, apoptosis resistance in fibroblast-like synoviocytes (FLS), immune dysregulation, and enhanced osteoclastogenesis. Recent studies further reveal stage-dependent and cell type-specific patterns of ER stress activation, underscoring its context-dependent pathogenic functions during disease initiation and progression. Accordingly, therapeutic strategies are shifting from broad suppression of ER stress toward precision modulation of discrete UPR modules, including alleviation of excessive proteostatic burden and selective induction of pro-apoptotic signaling in pathogenic synoviocytes. By integrating mechanistic insights with translational perspectives, this review highlights ER stress as a context-dependent signaling network and a potential precision therapeutic target in RA.