ArticleArthritis research & therapy2026
IRE1/p‑JNK/NRF2 axis-mediated GPX4 upregulation underlies ferroptosis resistance in rheumatoid arthritis fibroblast-like synoviocytes.
Article in Arthritis research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundRheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLS) exhibit chronic endoplasmic reticulum stress with activation of the IRE1/phospho‑JNK arm of the unfolded protein response; yet, they remain resistant to apoptosis. Although ferroptosis has been implicated in the pathogenesis of rheumatoid arthritis, the mechanisms underlying ferroptosis resistance in RA‑FLS remain poorly understood.
methodsA total of 17 patients who underwent joint replacement were included (RA n = 9; OA n = 8). Primary fibroblast-like synoviocytes (FLS; ≥3 donors per assay) were analyzed by RT-qPCR and western blotting for IRE1, p-JNK, NRF2 and GPX4. Signaling was modulated with siRNA or inhibitors against ERN1 or NRF2. Ferroptosis was assessed by transmission electron microscopy, lipid peroxidation, Fe²⁺ and glutathione depletion; cell phenotypes were evaluated by invasion, wound-healing and CCK-8 assays. In vivo (≥ 4 per group), a collagen-induced arthritis (CIA) rat model received the IRE1 inhibitor 4µ8c; micro-CT, joint pathology and biochemical markers were evaluated.
resultsRA-FLS showed elevated IRE1/p-JNK, increased total and nuclear NRF2, and higher GPX4 versus OA-FLS, and were more resistant to ferroptosis. ERN1 knockdown reduced p-JNK, NRF2 and GPX4 and increased lipid peroxidation, iron accumulation, glutathione loss and ferroptosis. NRF2 inhibition also sensitized RA-FLS to ferroptosis and attenuated aggressive phenotypes. In CIA rats, IRE1 inhibition partially attenuated bone destruction, lowered serum IL-1β/MMP9, and reduced synovial GPX4.
conclusionSustained IRE1/p-JNK/NRF2 signaling upregulates GPX4, linking ER stress to ferroptosis resistance in RA-FLS. Targeting IRE1 lowers GPX4 and restores ferroptotic sensitivity, suggesting a potential therapeutic strategy for RA.
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