N6-methyladenosine triggers renal fi brosis via enhancing translation and stability of ZEB2 mRNA

In recent years, a surge in studies investigating N6-methyladenosine (m(6)A) modification in human diseases has occurred. However, the specific roles and mechanisms of m(6)A in kidney disease remain incompletely understood. This study revealed that m(6)A 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 m(6)A sequencing, RNA-seq, and functional studies, we confirmed the pivotal involvement of zinc finger E-box binding homeobox 2 (ZEB2) in m(6)A-mediated RF and EMT. Notably, the m(6)A-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 dm(6)ACRISPR 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 m(6)A/ZEB2 on RF progression. Our findings highlight the m(6)A-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.