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

  • Cell Death Discov. 2025 Mar 15;11(1):104. doi: 10.1038/s41420-025-02384-1.
Jini Qiu  #  1  2 ,  Xueling Zhang  #  1  2 ,  Qian Shi  #  3 ,  Yujing Yang  #  1  2 ,  Rongmei Zhou  1  2 ,  Jun Xiang  1  2 ,  Jiayu Gu  1  2 ,  Jianjiang Xu  1  2 ,  Jiaxu Hong  4  5  6  7 ,  Kun Shan  8  9
Affiliations
  • 1. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China.
  • 2. NHC Key laboratory of Myopia and Related Eye Diseases, NHC, Shanghai, 200031, China.
  • 3. Department of Ophthalmology, Yixing Eye Hospital, Wuxi School of Medicine, Jiangnan University, Yixing, 214200, Jiangsu, China.
  • 4. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. [email protected].
  • 5. NHC Key laboratory of Myopia and Related Eye Diseases, NHC, Shanghai, 200031, China. [email protected].
  • 6. Shanghai Key Laboratory of Rare Disease Gene Editing and Cell Therapy, Shanghai Engineering Research Center of Synthetic Immunology, Shanghai, 200032, China. [email protected].
  • 7. Department of Ophthalmology, Children's Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, 201102, China. [email protected].
  • 8. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. [email protected].
  • 9. NHC Key laboratory of Myopia and Related Eye Diseases, NHC, Shanghai, 200031, China. [email protected].
  • # Contributed equally.
PMID: 40089501 DOI: 10.1038/s41420-025-02384-1
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 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. Schematic representation of METTL3-m6A-TGF-β signaling regulating FCED. In the context of environmental stress, METTL3 is upregulated in corneal endothelium, which in turn leads to increased m6A level of TGFB2 mRNA, upregulation of TGF-β2 protein via YTHDF1 mechanism, and activation of TGF-β signaling pathway. The regulation of these mechanisms results in the progressive irreversible transition of corneal endothelial cells from their specific phenotype to a mesenchymal phenotype, which accelerates the progression of FECD.

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