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<p>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 <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) during cEndMT process and FECD progression. The m<sup>6</sup>A writer methyltransferase-like 3 (METTL3) was significantly upregulated in FECD models and induced transcriptomic hypermethylation, including <i>TGFB2</i> mRNA. METTL3 promoted the translation of hypermethylated <i>TGFB2</i> 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<sup>6</sup>A-mediated mechanism in regulating cEndMT process, suggesting the prevailing role of m<sup>6</sup>A in cellular phenotypic transition. Targeting METTL3/m<sup>6</sup>A is a promising strategy for FECD treatment.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月15日

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  • Jini Qiu,
  • Xueling Zhang,
  • Qian Shi,
  • Yujing Yang,
  • Rongmei Zhou,
  • Jun Xiang,
  • Jiayu Gu,
  • Jianjiang Xu,
  • Jiaxu Hong,
  • Kun Shan

摘要

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 N6-methyladenosine (m6A) during cEndMT process and FECD progression. The m6A 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-m6A-mediated mechanism in regulating cEndMT process, suggesting the prevailing role of m6A in cellular phenotypic transition. Targeting METTL3/m6A is a promising strategy for FECD treatment.