2. Academic Validation
  3. RRM2 contributes to pathogenic phenotype of fibroblast-like synoviocytes by activating NF-κB signaling and inhibiting ferroptosis in rheumatoid arthritis

RRM2 contributes to pathogenic phenotype of fibroblast-like synoviocytes by activating NF-κB signaling and inhibiting ferroptosis in rheumatoid arthritis

  • J Orthop Surg Res. 2025 Nov 7;20(1):976. doi: 10.1186/s13018-025-06417-4.
Linqi Zhang 1,  Zhibing Wang 1,  Jingjie Zheng 1,  Qiulin Zhong 2
Affiliations

Affiliations

  • 1 Department of Orthopedics, Sichuan Mianyang 404 Hospital, 56 Yuejin Road, Mianyang, 621000, Sichuan, China.
  • 2 Department of Orthopedics, Sichuan Mianyang 404 Hospital, 56 Yuejin Road, Mianyang, 621000, Sichuan, China. [email protected].
PMID: 41204303 DOI: 10.1186/s13018-025-06417-4
Abstract

Objective: The development and pathogenesis of rheumatoid arthritis (RA) are associated with Ferroptosis. This study aims to investigate the regulatory role of ribonucleotide reductase subunit M2 (RRM2) in Ferroptosis and the pathogenic phenotype of fibroblast-like synoviocytes (FLSs) in RA.

Methods: Transcriptomic datasets associated with rheumatoid arthritis were analyzed to identify differentially expressed genes (DEGs), which were then intersected with known ferroptosis-related genes using a Venn diagram to determine overlapping candidates. The receiver operating characteristic (ROC) curve was utilized to evaluate the diagnostic value of key genes. The expression of RRM2 was silenced using short hairpin RNA transfection. Cell viability, motility, and invasive capacity were evaluated through the CCK-8 assay, scratch assay, Transwell, and ELISA assay, respectively. Inflammatory cytokines and ferroptosis-associated indicators were quantified using ELISA and specific biochemical detection kits. Additionally, the transcriptional and protein levels of genes linked to FLS function were analyzed.

Results: RRM2 was upregulated in tumor necrosis factor-alpha (TNF-α)-induced MH7A cells. Knockdown of RRM2 significantly inhibited TNF-α-induced cell proliferation, migration, invasiveness, and the release of pro-inflammatory cytokines in MH7A cells. Additionally, RRM2 knockdown induced Ferroptosis, as evidenced by increased Reactive Oxygen Species (ROS), ferrous iron (Fe2+), and malondialdehyde (MDA), alongside decreased expression of Glutathione Peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Further mechanistic analysis revealed that RRM2 led to nuclear factor-kappa B (NF-κB) signaling activation.

Conclusion: RRM2 inhibits Ferroptosis and enhances the pathogenic behavior of RA FLSs through activation of the NF-κB pathway, highlighting its pivotal contribution to RA development.

Keywords

Ferroptosis; Fibroblast-like synoviocytes; NF-κB signaling; RRM2; Rheumatoid arthritis.

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