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The Nrf2-GPX4 Pathway Provides Protection Against Rheumatoid Arthritis via Inhibition of Macrophage

Bingxue Liang1, Long Li1, Xiang Ma1

  • 1College of Acupuncture and Tuina, Chongqing University of Chinese Medicine, Chongqing, China.

Journal of Biochemical and Molecular Toxicology
|October 28, 2025
PubMed

Insights

Activating the Nrf2-GPX4 pathway can reduce rheumatoid arthritis (RA) by preventing macrophage ferroptosis and M1 polarization, thereby inhibiting synovial fibroblast proliferation. This discovery offers new therapeutic targets for RA.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pathogenesis of Rheumatoid Arthritis

Background:

  • Rheumatoid arthritis (RA) involves abnormal activation and proliferation of synovial fibroblasts (RASFs).
  • The precise mechanisms driving RASF activation in RA remain unclear.
  • Understanding these mechanisms is crucial for developing effective RA treatments.

Purpose of the Study:

  • To investigate the role of the Nrf2-GPX4 pathway in regulating RASF activation in RA.
  • To explore the therapeutic potential of activating the Nrf2-GPX4 pathway in RA models.

Main Methods:

  • Utilized a complete Freund's adjuvant (CFA)-induced adjuvant-induced arthritis (AIA) rat model.
  • Administered Nrf2 activator CDDO-EA to assess its effects on macrophage ferroptosis and inflammation.
  • Evaluated the impact of Nrf2-GPX4 activation on RASF proliferation in vitro.
  • Used ferroptosis inducer RSL-3 to validate the role of ferroptosis.

Main Results:

  • Nrf2 and GPX4 protein levels were reduced in AIA rat synovial tissues.
  • CDDO-EA treatment decreased inflammatory markers (TNF-α, IL-6) and ferroptosis indicators (MDA, Fe2+) while increasing antioxidants (SOD, GSH).
  • Nrf2-GPX4 activation suppressed macrophage ferroptosis and M1 polarization, and inhibited RASF proliferation in vitro.
  • The protective effects of Nrf2-GPX4 were partially reversed by RSL-3.

Conclusions:

  • The Nrf2-GPX4 pathway plays a critical role in regulating macrophage ferroptosis and M1 polarization.
  • Activated Nrf2-GPX4 effectively suppresses RASF proliferation, offering a potential therapeutic strategy for RA.
  • This study highlights the Nrf2-GPX4 pathway as a novel target for RA treatment.
Keywords:
GPX4M1 polarizationNrf2ferroptosismacrophagesrheumatoid arthritisrheumatoid arthritis synovial fibroblasts

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