NSUN2 promotes PM2.5-induced epithelial-mesenchymal transition through methylating chitinase 3-like-1 mRNA

Chitinase 3-like-1 (CHI3L1) is an emerging biomarker and therapeutic target for prediction and evaluation of respiratory diseases. However, the functions and underly molecular mechanisms on the regulation of CHI3L1 in PM_2.5-induced pulmonary fibrosis are unclear. In the present study, we found that increased expressions of NSUN2 and the m⁵C methylation of CHI3L1 mRNA in PM_2.5-treated lung tissues and alveolar epithelial MLE-12 cells were observed. NSUN2 could catalyze m⁵C methylation of CHI3L1 at the 3'UTR, thereby promoting the transport of CHI3L1 mRNA to cytoplasm in an Aly/REF export factor (ALYREF) dependent manner. Under PM_2.5 exposure, NSUN2 deficiency could counterbalance PM_2.5-induced CHI3L1 m⁵C methylation and epithelial-mesenchymal transition (EMT) in vivo and in cells. Our research collectively offers new molecular understanding regarding the mechanisms behind pulmonary fibrosis induced by PM_2.5 exposure.