EULAR rheumatology open · 2026
4-Octyl itaconate inhibits synovial fibroblast activation by targeting Nrf2 to exert anti-inflammatory effects in rheumatoid arthritis.
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Andersen Benedicte B, Kemble Samuel, Greisen Stinne, Thyrsted Jacob, Schack Vivien R, Fuchs Elisabeth, Hansen Anne L, Poulsen Thomas B, Holm Christian K, Olagnier David, Croft Adam, Deleuran Bent, Nielsen Morten A
Аннотация
OBJECTIVES: Fibroblast-like synoviocytes (FLS) are pivotal for the expansive growth and invasiveness of rheumatoid synovitis, and patients with a fibroblastic-rich pathotype respond poorly to currently approved antirheumatic drugs. The aim of this project was to examine the anti-inflammatory effects of the nuclear factor erythroid 2-related factor 2 (Nrf2) activator 4-octyl itaconate (4-OI) on inflammatory rheumatoid arthritis (RA)-FLS-dominated pathology.
METHODS: Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and autologous cocultures of RA-FLS and peripheral blood mononuclear cells were cultured with 4-OI, corticosteroids or antitumor necrosis factor alpha antibodies and analysed for inflammatory activity with Western blot and enzyme-linked immunosorbent assay. 4-OI-induced transcription factor Nrf2 was genetically ablated in immortalised FLS using Clustered Regurlarly Interspaced Short Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) gene editing.In vivo, 4-OI was administered intraarticularly in the monoarticular methylated bovine serum albumin antigen-induced arthritis model and intraperitoneally in the collagen-induced arthritis, with subsequent clinical evaluation.
RESULTS: In RA-FLS in both monocultures and autolog cocultures, 4-OI treatment mediated an increase in gene expression of the Nrf2-regulated protein heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1 with a concomitant decrease in monocyte chemoattractant protein-1 and specifically in monocultures also of interleukin 6 secretion. Silencing of Nrf2 reduced the effect mediated by 4-OI in RA-FLS. In the methylated bovine serum albumin mouse model, local administration of 4-OI significantly reduced joint swelling. In the collagen-induced arthritis model, a similar trend was seen accompanied by a significant reduction of interleukin 6 in serum.
CONCLUSIONS: 4-OI ameliorates inflammation in models of RA, particularly in FLS-driven disease pathology. Overall, human in vitro data and murine in vivo data provide mechanistic insights into the role of 4-OI-induced activation of Nrf2 directly reducing the activation of inflammatory FLS in RA.
METHODS: Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and autologous cocultures of RA-FLS and peripheral blood mononuclear cells were cultured with 4-OI, corticosteroids or antitumor necrosis factor alpha antibodies and analysed for inflammatory activity with Western blot and enzyme-linked immunosorbent assay. 4-OI-induced transcription factor Nrf2 was genetically ablated in immortalised FLS using Clustered Regurlarly Interspaced Short Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) gene editing.In vivo, 4-OI was administered intraarticularly in the monoarticular methylated bovine serum albumin antigen-induced arthritis model and intraperitoneally in the collagen-induced arthritis, with subsequent clinical evaluation.
RESULTS: In RA-FLS in both monocultures and autolog cocultures, 4-OI treatment mediated an increase in gene expression of the Nrf2-regulated protein heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1 with a concomitant decrease in monocyte chemoattractant protein-1 and specifically in monocultures also of interleukin 6 secretion. Silencing of Nrf2 reduced the effect mediated by 4-OI in RA-FLS. In the methylated bovine serum albumin mouse model, local administration of 4-OI significantly reduced joint swelling. In the collagen-induced arthritis model, a similar trend was seen accompanied by a significant reduction of interleukin 6 in serum.
CONCLUSIONS: 4-OI ameliorates inflammation in models of RA, particularly in FLS-driven disease pathology. Overall, human in vitro data and murine in vivo data provide mechanistic insights into the role of 4-OI-induced activation of Nrf2 directly reducing the activation of inflammatory FLS in RA.