Fig. 1: The ferroptosis inducer IKE modulated joint inflammation and tissue damage.

a Left, representative immunohistochemical staining of 8-OHdG in hyperplastic rheumatoid synovium of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and in the inflamed joint tissue of collagen-induced arthritis (CIA) model mice. Scale bars, 100 μm. Right, Quantitative comparison of 8-OHdG in RA and OA patients (n = 26 RA patients; n = 21 OA patients). ****P < 0.0001 (two-tailed t-test). b Left, representative immunohistochemical staining of 4-HNE in hyperplastic rheumatoid synovium of RA and OA patients and in the inflamed joint tissue of CIA model mice. Scale bars, 100 μm. Right, Quantitative comparison of 4-HNE in RA and OA patients (n = 26 RA patients; n = 21 OA patients). ****P < 0.0001 (two-tailed t-test). c Representative fluorescent multiplex IHC staining (left panel) and quantification (right panel) of RA joint synovium labeled with anti-VCAM-1 (red), anti-CD248 (green), anti-4-HNE (light blue), and DAPI (blue). Scale bars, 200 μm. ns, P = 0.3804 (two-tailed t-test). d MDA concentration in the joint fluid of RA patients with different disease activities. *P = 0.0274 (two-tailed t-test). e Total iron concentrations in the joint fluid of RA patients. *P = 0.0365 (two-tailed t-test). High disease activity, n = 12 RA patients; moderate disease activity, n = 8 RA patients (d and e). Joint inflammation was measured by arthritis score (f) (**P = 0.0011; ns, P = 0.8455; one-way ANOVA followed by multiple comparisons was performed to compare the means of arthritis score at the end point) and paw thickness (g) (**P = 0.0037; ns, P = 0.5670; one-way ANOVA followed by multiple comparisons) in CIA mice intraperitoneally injected with 40 mg/kg IKE every day and/or 10 mg/kg liproxstain-1 (Lip-1) every 2 days for 22 days. n = 9 mice for CIA + Vehicle and CIA + IKE group, n = 8 mice for CIA + Lip-1 and CIA + IKE + Lip-1 group. h Representative micro-computed tomography (micro-CT) images of control and CIA model mice with or without IKE treatment. i Images of hematoxylin and eosin (H&E), toluidine blue O, and safranin O staining of representative joints in control and CIA mice with or without IKE treatment at day 22 after treatment initiation. Scale bars, 100 μm. j Quantification of the histomorphometric analysis of cartilage damage, bone erosion, and pannus formation. ****P < 0.0001, ***P = 0.0006; two-tailed t-test. n = 9 joints for CIA group, n = 12 joints for CIA + IKE group. Data in f and g are presented as mean ± SEM. Other data are presented as mean ± SD. Source data are provided as a Source data file.