NAT10 accelerates pulmonary fibrosis through N4-acetylated TGFB1-initiated epithelial-to-mesenchymal transition upon ambient fine particulate matter exposure

Exposure to ambient fine particulate matter (PM2.5) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM2.5-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM2.5 to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C “writer” protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability of transforming growth factor beta 1 (TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM2.5 exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM2.5-triggered pulmonary fibrosis via increasing TGFB1 mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM2.5-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism. [Display omitted] •NAT10-mediated RNA acetylation accelerates PM2.5-induced pulmonary fibrosis.•NAT10 enhances TGFB1 mRNA stability in an RNA acetylation-dependent manner.•TGFB1 reverses the protection of NAT10 depletion on PM2.5-induced pulmonary fibrosis.