Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.

Aberrant number and/or dysfunction of CD4⁺Foxp3⁺ Regulatory T cells (T_regs) are associated with the pathogenesis of rheumatoid arthritis (RA). A previous study has demonstrated that thymus-derived, natural T_regs (nT_regs) prefer to accumulate in inflamed joints and transdifferentiate to T_H17 cells under the stimulation of inflamed synovial fibroblasts (SFs). In this study, we made a head-to-head comparison of both T_reg subsets and demonstrated that induced T_regs (iT_regs), but not nT_regs, retained Foxp3 expression and regulatory function on T effector cells (T_effs) after being primed with inflamed SFs. In addition, iT_regs inhibited proliferation, inflammatory cytokine production, migration, and invasion ability of collagen-induced arthritis (CIA)–SFs in vitro and in vivo. Moreover, we noted that iT_regs directly targeted inflamed SFs to treat autoimmune arthritis, while nT_regs failed to do this. Thus, manipulation of the iT_reg subset may have a greater potential for prevention or treatment of patients with RA.

Objective: To evaluate the utility of synovial iron quantification using Magnetic resonance imaging (MRI) in assessing structural joint damage in the knee of patients with rheumatoid arthritis (RA). Methods: This cross-sectional study employed a two-stage design. In the initial comparative stage, 6 patients with RA and 5 patients with osteoarthritis (OA) were recruited to compare synovial R2* values, a metric derived from iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ) MRI sequences representing synovial iron content. Following this, the RA cohort was expanded to a total of 51 patients to investigate the association between R2* values and clinical parameters, including disease activity and bone erosion. Synovial fluid iron levels were measured with an Iron Assay Kit and synovial iron deposits were semi-quantified via Prussian blue staining. Associations between R2* and clinical and laboratory parameters, including inflammatory factors and joint damage indices, were analyzed using Spearman’s rank correlation. Univariate and multivariate ordered logistic regression models were employed to identify factors associated with bone erosion severity. An R2*-based nomogram was developed and validated using receiver operating characteristic (ROC) analysis and calibration curves. Results: Synovial R2* values were significantly higher in RA patients than those with osteoarthritis (53.66 S⁻¹ vs. 31.38 S⁻¹, p < 0.05), consistent with Prussian blue staining results. While synovial R2* values showed no significant correlation with systemic iron metabolic markers, inflammatory indicators, or the Disease Activity Score 28, they were positively correlated with bone erosion severity (ρ = 0.500, p < 0.001) and negatively associated with the joint space width (ρ = −0.307, p < 0.05). Multivariate analysis identified R2* as an independent indicator linked to bone erosion extent (OR = 2358.336, p < 0.001). The R2*-based nomogram demonstrated good discriminative performance. (AUC = 0.83). Conclusions: The R2* value derived from IDEAL-IQ MRI is a reliable tool for quantifying synovial iron and may represent a promising non-invasive imaging biomarker reflecting bone erosion in RA patients.

Rheumatoid arthritis (RA) is a leading cause of disability globally. Although iron accumulation in arthritic lesions has been observed in patients with RA, its specific contribution to disability outcomes remains unclear. Here we demonstrate a comprehensive multiomics approach to elucidate the impact and underlying mechanisms of iron overload in RA. First, clinical radiology in an RA cohort reveals a positive correlation between elevated ferrous iron levels in synovial fluid and joint damage extent. Iron chelator DFO administration significantly alleviates bone destruction in the K/BxN serum-transfer induced arthritis mice model. In terms of cellular function, we identify the aggressive migration and invasion of fibroblast-like synoviocytes (FLSs) induced by excess iron utilizing a humanized synovitis model. Mechanistically, the multiomics integration of transcriptomics and metabolomics indicates the enriched lipid synthesis pathway in the FLS response to iron exposure. The lipid transcription factor SREBP1 is particularly highly expressed in RA-FLSs, and its genetic ablation or pharmacological inhibition markedly mitigates the pathogenic effects of iron overload both in vitro and in vivo. At the molecular level, iron regulatory protein IRP1 enhances the translation of SREBP1 adapter protein SCAP by disengaging from its mRNA 5′ untranslated region upon iron stimulation. This process facilitates SREBP1 cleavage and activation, driving the upregulation of genes involved in fatty acid and cholesterol biosynthesis. Our findings elucidate the IRP1–SCAP axis as a critical modulator of lipid metabolic reprogramming in aggressive FLSs, underscoring its potential as a therapeutic target for RA by modulating the ‘iron–lipid’ crosstalk.

Objective: Anaemia is common in rheumatoid arthritis (RA), but the role of erythroid-lineage cells is unclear. We investigated the function of CD45 ⁺ erythroid progenitor cells (CD45 ⁺ EPCs) in RA. Methods: We analysed CD45 ⁺ EPC frequency in patients with RA and mice with collagen-induced arthritis (CIA). Transcriptomics, functional studies and mechanistic assays (Transwell and dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR) were used. Therapeutic potential was tested in RA synovial organoids and via splenectomy/adoptive transfer in mice with CIA. Results: CD45 ⁺ EPCs were expanded in RA circulation and CIA mouse spleens, correlating positively with disease activity and negatively with haemoglobin. They displayed an immunosuppressive transcriptome, enriched for transforming growth factor (TGF)-β and chemokine signalling. RA-derived CD45 ⁺ EPCs showed enhanced proliferation and TGF-β/reactive oxygen species production. High C-C Motif Chemokine Receptor 2 (CCR2) expression made them susceptible to recruitment by macrophage-derived C-C Motif Chemokine Ligand 2 (CCL2). In RA synovial organoids, CD45 ⁺ EPCs suppressed growth and inflammation via TGF-β, while organoid-conditioned media promoted their migration via CCL2. Recruited CD45 ⁺ EPCs suppressed M1 and promoted M2-like macrophage polarisation. The transcription factor SPI1 was upregulated in RA CD45 ⁺ EPCs, bound the TGFB1 promoter and drove TGF-β production. In vivo, splenectomy worsened CIA, whereas adoptive transfer of CD45 ⁺ EPCs ameliorated arthritis. Conclusion: We identify CD45 ⁺ EPCs as a novel, SPI1-driven immunosuppressive population in RA. Recruited via the CCR2-CCL2 axis, they attenuate inflammation by modulating macrophages through SPI1/TGF-β signalling, revealing a new immunoregulatory axis and potential therapeutic targets.