Osthole Regulates N6-methyladenosine-modified TGM2 to Inhibit the Progression of Rheumatoid Arthritis and Associated Interstitial Lung Disease

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and RA interstitial lung disease (ILD) is a severe complication of RA. This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from , , and plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA-ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA-fibroblast-like synoviocytes (FLS) by attenuating NF-κB signaling, resulting in the suppression of RA progression. Interestingly, WTAP-mediated N6-methyladenosine modification of TGM2 and Myc-mediated WTAP transcription cooperatively contributed to the formation of a TGM2/Myc/WTAP-positive feedback loop through upregulating NF-κB signaling. Moreover, OS could downregulate the activation of the TGM2/Myc/WTAP-positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b macrophages, and the effectiveness and non-toxicity of OS in suppressing RA and RA-ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS-regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA-ILD treatment.