Endoplasmic Reticulum Stress in Rheumatoid Arthritis: Mechanisms, Pathogenic Roles, and Therapeutic Opportunities

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation, synovial hyperplasia, and joint destruction. Accumulating evidence implicates endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as key contributors to RA pathogenesis. This review consolidates recent findings on how ERS-related pathways—including PERK-eIF2α-ATF4, IRE1-XBP1, and ATF6—interact with immune, inflammatory, and apoptotic mechanisms in RA. It also examines the molecular connections between HLA-linked susceptibility, protein citrullination, and synovial cell dysfunction. Persistent ERS promotes synoviocyte proliferation, cytokine production, and angiogenesis, sustaining chronic inflammation and tissue damage. Targeting UPR mediators such as GRP78, PERK, and IRE1 shows promise for modulating inflammation and inducing apoptosis in fibroblast-like synoviocytes. Novel pharmacological agents—including salubrinal, STF-083010, and proteasome inhibitors—demonstrate disease-modifying potential in preclinical models. A detailed understanding of ERS signaling offers new perspectives for precision therapies in RA. Modulating the UPR may restore immune balance and reduce treatment resistance, highlighting ERS pathways as emerging therapeutic targets in autoimmune arthritis..