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This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from <jats:italic>Cnidium<\/jats:italic>, <jats:italic>Angelica<\/jats:italic>, and <jats:italic>Citrus<\/jats:italic> plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA\u2010ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA\u2010fibroblast\u2010like synoviocytes (FLS) by attenuating NF\u2010\u03baB signaling, resulting in the suppression of RA progression. Interestingly, WTAP\u2010mediated N6\u2010methyladenosine modification of TGM2 and Myc\u2010mediated WTAP transcription cooperatively contributed to the formation of a TGM2\/Myc\/WTAP\u2010positive feedback loop through upregulating NF\u2010\u03baB signaling. Moreover, OS could downregulate the activation of the TGM2\/Myc\/WTAP\u2010positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b<jats:sup>+<\/jats:sup> macrophages, and the effectiveness and non\u2010toxicity of OS in suppressing RA and RA\u2010ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS\u2010regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA\u2010ILD treatment.<\/jats:p>","DOI":"10.1002\/mco2.219","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T15:19:04Z","timestamp":1677079144000},"source":"Crossref","is-referenced-by-count":21,"title":["Osthole regulates N6\u2010methyladenosine\u2010modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease"],"prefix":"10.1002","volume":"4","author":[{"given":"Xian","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Rheumatism and Immunology Peking University Shenzhen Hospital  Shenzhen China"},{"name":"Institute of Immunology and Inflammatory Diseases Shenzhen Peking University\u2010The Hong Kong University of Science and Technology Medical Center; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatism and Immunology Peking University Shenzhen Hospital  Shenzhen China"},{"name":"Institute of Immunology and Inflammatory Diseases Shenzhen Peking University\u2010The Hong Kong University of Science and Technology Medical Center; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Tao","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Medical University  Dongguan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianxiang","family":"Luo","sequence":"additional","affiliation":[{"name":"The Marine Biomedical Research Institute Guangdong Medical University  Zhanjiang China"},{"name":"The Marine Biomedical Research Institute of Guangdong Zhanjiang  Zhanjiang 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