N6-methyladenosine triggers renal fibrosis via enhancing translation and stability of ZEB2 mRNA.

In recent years, a surge in studies investigating N6-methyladenosine (mA) modification in human diseases has occurred. However, the specific roles and mechanisms of mA in kidney disease remain incompletely understood. This study revealed that mA plays a positive role in regulating renal fibrosis (RF) by inducing epithelial-to-mesenchymal phenotypic transition (EMT) in renal tubular cells. Through comprehensive analyses, including mA sequencing, RNA-seq, and functional studies, we confirmed the pivotal involvement of zinc finger E-box binding homeobox 2 (ZEB2) in mA-mediated RF and EMT. Notably, the mA-modified coding sequence of ZEB2 mRNA significantly enhances its translational elongation and mRNA stability by interacting with the YTHDF1/eEF-2 complex and IGF2BP3, respectively. Moreover, targeted demethylation of ZEB2 mRNA using the dmACRISPR system substantially decreases ZEB2 expression and disrupts the EMT process in renal tubular epithelial cells. In vivo and clinical data further support the positive influence of mA/ZEB2 on RF progression. Our findings highlight the mA-mediated regulation of RF through ZEB2, revealing a novel therapeutic target for RF treatment and enhancing our understanding of the impact of mRNA methylation on kidney disease.