Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis

• DOI: 10.1016/j.redox.2023.103008
• Publication Date: 2023-12-20T02:43:34Z
• Authors: Yan Liu; Xiqing Luo; Ye Chen; Junlong Dang; Donglan Zeng; Xinghua Guo; Weizhen Weng; Jun Zhao; Xiaoyi Shi; Jingrong Chen; Bo Dong; Shuyuan Zhong; Jianhua Ren; Yuhang Li; Julie Wang; Jingwen Zhang; Jianbo Sun; Hanshi Xu; Yan Lu; David Brand; Song Guo Zheng; Yunfeng Pan
• Keywords: 0301 basic medicine; Medicine (General); 03 medical and health sciences; R5-920; Macrophage; QH301-705.5; Iron overload; Ferroptosis; Rheumatoid arthritis; Biology (General); GPX4; Research Paper

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