METTL3-m6A-mediated TGF-β signaling promotes Fuchs endothelial corneal dystrophy via regulating corneal endothelial-to-mesenchymal transition

作者：Jini Qiu, Xueling Zhang, Qian Shi, Yujing Yang, Rongmei Zhou, Jun Xiang, Jiayu Gu, Jianjiang Xu, Jiaxu Hong, K. Y. Shan · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02384-1 · 被引用次数：8 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Circular RNAs in diseases

Abstract Fuchs endothelial corneal dystrophy (FECD) is the leading cause of vision-threatening corneal endothelial dystrophy without pharmacologic treatments. Corneal endothelial-mesenchymal transition (cEndMT), a specific cellular phenotypic transition, is implicated in the vicious cycle in FECD pathogenesis. Here, we investigated the reversible epigenetic regulation of N 6 -methyladenosine (m 6 A) during cEndMT process and FECD progression. The m 6 A writer methyltransferase-like 3 (METTL3) was significantly upregulated in FECD models and induced transcriptomic hypermethylation, including TGFB2 mRNA. METTL3 promoted the translation of hypermethylated TGFB2 mRNA in an YTHDF1-dependent manner, resulting in upregulation of TGF-β2 protein and activation of TGF-β signaling. Intervention of METTL3 expression or catalytic activity could suppress TGF-β signaling activation, subsequently ameliorate cEndMT process and FECD progression. This study reveals unique METTL3-m 6 A-mediated mechanism in regulating cEndMT process, suggesting the prevailing role of m 6 A in cellular phenotypic transition. Targeting METTL3/m 6 A is a promising strategy for FECD treatment.