Iron overload reprogramming lipid metabolism through the IRP1–SCAP axis in fibroblast-like synoviocytes aggravates bone destruction in rheumatoid arthritis

www.nature.com/emm ARTICLE OPEN Iron overload reprogramming lipid metabolism through the IRP1–SCAP axis in fibroblast-like synoviocytes aggravates bone destruction in rheumatoid arthritis ✉ Yan Liu 1,5 , Linkai Fang1,5, Manli Wang1,5, Shuyuan Zhong1, Yiding Xiong2, Yuluan Hou3, Jianhua Ren4, Yuhang Li4, Weihang Zhu1, ✉ ✉ 1 Xia Meng , Chenyang Lu 1 and Yunfeng Pan 1 1234567890();,: © The Author(s) 2026 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01710-6 Graphical Abstract INTRODUCTION Synovial hyperplasia and pannus formation are hallmark pathological features of rheumatoid arthritis (RA)1. Fibroblast-like synoviocytes (FLSs), the predominant mesenchymal cells in synovial tissue, exhibit neoplastic-like characteristics, including resistance to apoptosis, uncontrolled proliferation, chronic inflammation and enhanced migration and invasion2. These aggressive behaviors drive synovial hyperplasia and subsequent bone erosion, creating a high energy demand supported by vigorous metabolism, such as glycolysis, mitochondrial oxidative phosphorylation, lipogenesis and amino acid synthesis3,4. Therefore, elucidating and targeting the metabolic dysregulation in FLSs may open a promising therapeutic avenue to disrupt the inflammatory and destructive cascade in RA. 1 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 2Division of Rheumatology and Immunology, Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 4Department of Joint and Trauma Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 5These authors contributed equally: Yan Liu, Linkai Fang, Manli Wang. ✉email: ; ; Received: 7 July 2025 Revised: 23 January 2026 Accepted: 3 February 2026 Y. Liu et al. 2 Synovial cells are driven into the pathogenic activated states by multiple stimuli in the adverse microenvironment of RA. Among these, aberrant iron levels have attracted considerable attention. Iron, as an essential trace element for cellular functions, plays a critical role in the development of the nervous, cardiovascular, hematological and immune systems5. However, disruptions in iron homeostasis are implicated in a variety of pathological conditions, including ischemia–reperfusion injuries6, degenerative diseases7 and metabolic disorders8, primarily owing to the peroxide damage and proinflammatory effects induced by excess iron. Our previous research revealed distinct ferroptosis outcomes in M1-like and M2like macrophage subsets following iron overload in joints, exacerbating local immune disorders in RA9. However, the specific effects of excess articular iron on FLSs, particularly its role in synovial proliferation and bone destruction in RA, remain to be determined. Understanding whether iron-immersed FLS contribute to these pathological processes and elucidating how iron influences the metabolic characteristics of RA-FLSs require further investigation. In the present study, we explore the impact of iron overload on FLSs in RA pathogenesis, utilizing the K/BxN serum-transfer induced arthritis (STIA) and humanized synovitis mouse models. Our findings reveal that the elevated ferrous iron promotes RAFLSs hyperplasia and invasion by activating SREBP1-mediated de novo lipogenesis. Mechanistically, we identify for the first time that the iron regulatory protein IRP1 binds to the 5′ untranslated region (5′ UTR) of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) mRNA, an adapter protein crucial for SREBP1 cleavage, translocation and activation. Under iron-replete conditions, IRP1 dissociates from SCAP mRNA, enhancing its translation and subsequently activating SREBP1. This process transcriptionally upregulates downstream genes involved in fatty acid and cholesterol biosynthesis to fuel the aggressive capacity of RA-FLSs. These discoveries highlight IRP1–SCAP interaction as a pivotal signal nexus linking extracellular iron overload to intracellular metabolic reprogramming in FLSs, and this ‘iron–lipid’ crosstalk represents a promising therapeutic strategy for RA. The STIA model was induced as described previously10. In brief, 100 μl arthritogenic K/BxN mice sera were administered intraperitoneally to 8week-old female C57BL/6 mice on day 0 and day 2. Arthritis severity was evaluated daily using a semiquantitative scoring system ranging from 0 to 4, where 0 means no evidence of erythema and swelling, 1 means mildly detectable swelling in a single digit, 2 means mild swelling extending to more than one digit, 3 means moderate swelling of the ankle and digits and 4 means severe swelling encompassing the ankle, paw and digits. All assessors were blinded to the group conditions. At day 9, mice were killed, and samples were collected for following experiments. Each animal was considered as an individual experimental unit. The humanized synovitis mouse model was utilized to assess the migration and invasion (...truncated)