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 m 5 C methylation of CHI3L1 mRNA in PM 2.5 -treated lung tissues and alveolar epithelial MLE-12 cells were observed. NSUN2 could catalyze m 5 C 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 m 5 C 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. The scheme for the proposed mechanism of NSUN2 promotes PM 2.5 -induced epithelial-mesenchymal transition (EMT) through methylating chitinase 3-like-1 (CHI3L1) mRNA. PM 2.5 increases NSUN2 expression and promotes the translation of CHI3L1, thereby regulating the expression of mesenchymal cell markers and EMT-inducing transcription factors in vivo and in cells. NSUN2 deficiency significantly alleviates PM 2.5 -induced EMT. • NSUN2 expression is upregulated in PM 2.5 -treated pulmonary tissues and cells. • NSUN2-mediated CHI3L1 mRNA methylation accelerates PM 2.5 -induced EMT and fibrosis. • NSUN2 enhances CHI3L1 mRNA stability and nuclear export in ALYREF-dependent manner. • NSUN2/CHI3L1/ERK/AKT is the key pathway in pulmonary fibrosis upon PM 2.5 exposure.