mA methyltransferase ZC3H13 improves pulmonary fibrosis in mice through regulating Bax expression.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease. N6-methyladenosine (mA) is a reversible RNA modification that was shown to be associated with IPF development. The present study aimed to explore the function and potential mechanism of the mA methylation enzyme zinc finger CCCH-type containing 13 (ZC3H13) in IPF. In the study, bioinformatic screening yielded a differentially expressed mA gene, ZC3H13, which was down-regulated in GEO microarrays, BLM-induced mouse models, and cellular models. Overexpression of ZC3H13 reduced histopathological damage of lung tissues in mice, mitigated fibrosis (including reduced α-SMA, collagen Ⅰ, and Vimentin levels, and elevated E-cadherin levels), decreased lung/body weight ratio and lung hydroxyproline levels, reduced oxidative stress (increased SOD activity and GSH-Px activity and decreased MDA levels), suppressed apoptosis within lung tissues and MLE-12 cells, promoted Bcl-2 expression, and inhibited Bax expression. Bax expression was found to be negatively correlated with ZC3H13 expression by correlation analysis. ZC3H13 could bind Bax mRNA and promote its mA methylation through reading protein YTHDC1, thereby inhibiting its stability. Bax inhibition ameliorated BLM-induced MLE-12 cell dysfunction and partially abrogated the inhibition of MLE-12 cell function by ZC3H13 downregulation. In conclusion, mA methyltransferase ZC3H13 impedes lung epithelial cell apoptosis and thus improves pulmonary fibrosis by promoting Bax mRNA mA methylation and down-regulating Bax expression through reading protein YTHDC1.