Dihydroartemisinin, a novel YTHDF2 inhibitor, alleviates rheumatoid arthritis by suppressing neutrophil extracellular traps via an autophagy-dependent pathway

  • Phytomedicine. 2026 Jul:156:158239. doi: 10.1016/j.phymed.2026.158239.
Zhaoran Wang  1 ,  Yi Jiao  2 ,  Tong Shi  1 ,  Chaoying Wen  1 ,  Jiahe Xu  3 ,  Tiantian Deng  4 ,  Yan Wang  4 ,  Tingting Deng  5 ,  Cheng Huang  6 ,  Yuan Xu  7 ,  Cheng Xiao  8
Affiliations
  • 1. China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100029, China; Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China.
  • 2. Department of Emergency, China-Japan Friendship Hospital, Beijing 100029, China.
  • 3. Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.
  • 4. Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China; Beijing University of Chinese Medicine, China-Japan Friendship Hospital Clinical Medicine, Beijing 100029, China.
  • 5. Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China.
  • 6. Department of Orthopaedic Surgery, China-Japan Friendship Hospital, Beijing, China. Electronic address: [email protected].
  • 7. Department of TCM Rheumatology, China-Japan Friendship Hospital, Beijing, China. Electronic address: [email protected].
  • 8. China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100029, China; Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China; Department of Emergency, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: [email protected].
PMID: 42068879 DOI: 10.1016/j.phymed.2026.158239
Abstract

Introduction: Neutrophil extracellular traps (NETs) are pivotal in the pathogenesis of rheumatoid arthritis (RA). Although dihydroartemisinin (DHA) has shown efficacy in arthritis animal models, its mechanism of NETs regulation remains unknown.

Objectives: Given the emerging role of m6A modification in immune cell activation, we investigated whether DHA alleviates RA by targeting an m6A-related mechanism in neutrophils.

Methods: We evaluated the therapeutic effect of DHA in collagen-induced arthritis (CIA) and K/BxN serum arthritis models. NETs were quantified by immunofluorescence and ELISA. Using transcriptomic data from RA patients, we identified key m6A regulators, which were validated in clinical samples. The target of DHA was verified through molecular docking, molecular dynamics simulations and a CETSA. The specific molecular mechanism through which DHA mediates neutrophil activation was elucidated through RIP-qPCR and mRNA stability assay.

Results: DHA significantly alleviated arthritis and inhibited NETs formation both in vivo and in vitro. We found that the protein YT521-B homology domain family protein 2 (YTHDF2), an m6A reader, is highly upregulated in RA neutrophils and critical for NETs formation. DHA directly binds to YTHDF2 and inhibits its function. Mechanistically, YTHDF2 recognizes m6A modifications on mTOR mRNA to promote its degradation, thereby driving NETs formation. Consequently, by targeting YTHDF2, DHA stabilized mTOR mRNA and inhibited NETs formation.

Conclusion: Our research showed that the YTHDF2-mTOR-NETs axis is a novel pathogenic axis in RA. We further demonstrated that DHA, as a novel YTHDF2 Inhibitor, acts through this axis, providing new mechanistic insights into RA pathogenesis and laying the foundation for targeting neutrophil m6A modification for the treatment of RA patients.

Keywords
Dihydroartemisinin; Neutrophil; Rheumatoid arthritis; YT521-B homology domain family protein 2 (YTHDF2); mTOR.
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