METTL3-mediated m6A Methylation Modification Promotes the Endothelial Cell Pyroptosis in Kawasaki Disease

Kawasaki disease (KD) is classified as an acute febrile illness characterized primarily by systemic vasculitis. While the involvement of N6-methyladenosine (m6A) modification in various cardiovascular conditions has been established, its specific role in KD remains unexplored. This study aims to investigate the potential influence of m6A modification in KD and to elucidate the mechanisms involved. Clinically, 18 KD patients and 15 healthy volunteers were recruited. Reverse transcription-quantitative polymerase chain reactio (RT-qPCR) was performed to assess the expression of m6A-related enzymes. Lactate dehydrogenase (LDH) release, interleukin (IL)-1β and IL-18 concentrations were analyzed by commercial kits. Hoechst 33,342/PI staining was performed for cell death detection. Pyroptosis-related protein levels were detected by Western blot. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were performed to assess the interaction between methyltransferase-like protein 3 (METTL3) and Nod-like receptor (NLR) family CARD domain-containing protein 4 (NLRC4). Finally, a KD mouse model was induced by Candida albicans cell wall extracts. Results showed that serum from KD patients exhibited higher METTL3 expression. Additionally, KD serum-treated THP1 cells induced pyroptosis of human umbilical vein endothelial cells (HUVECs). Mechanistically, METTL3 promoted the stability of NLRC4 mRNA via m6A methylation. Furthermore, NLRC4 overexpression promoted pyroptosis in KD-treated HUVECs. Finally, METTL3 inhibition attenuated coronary arteritis and pyroptosis in a KD mouse model. In summary, this study concluded that METTL3-mediated m6A methylation modification promoted the endothelial cell pyroptosis in KD, which might provide a reference for the pathogenesis of KD.