Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Dihydroartemisinin, a novel YTHDF2 inhibitor, alleviates rheumatoid arthritis by suppressing neutrophil extracellular traps via an autophagy-dependent pathway.
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Wang Zhaoran, Jiao Yi, Shi Tong, Wen Chaoying, Xu Jiahe, Deng Tiantian, Wang Yan, Deng Tingting, Huang Cheng, Xu Yuan, Xiao Cheng
Аннотация
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.
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.