m<sup>6</sup>A hypomethylation assembles a fibrogenic TCF7L2–Smad2/3 complex in pterygium

Xin Zhang; Yue Li; Xiaoyan Zhang; Chuanxi Yang; Yaping Jiang; Li Chen; Ming Xu; Yihui Chen

doi:10.1016/j.jgg.2026.04.026

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m⁶A hypomethylation assembles a fibrogenic TCF7L2–Smad2/3 complex in pterygium

doi: 10.1016/j.jgg.2026.04.026

a. Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China;
b. Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China;
c. Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai 200040, China;
d. Department of Cardiology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China

Funds:

This study was supported by the National Natural Science Foundation of China (82271050 and 82301175) and the Project of Key Disciplines of Medicine in the Yangpu District of Shanghai (22YPZA01).

Received Date: 2025-11-12
Accepted Date: 2026-04-30
Rev Recd Date: 2026-04-25

Available Online: 2026-05-07

Abstract

Abstract

Pterygium progression is driven by conjunctival fibroblast fibrosis, where TGF-β and Wnt signaling pathways promote fibrotic processes. However, the crosstalk between these pathways and the underlying epitranscriptomic mechanisms remains poorly understood. In this study, we identify a TCF7L2–Smad2/3 transcriptional complex that mediates key cellular and pathogenic events in pterygium. UV radiation or inflammatory stimuli suppress METTL3 expression in human conjunctival fibroblasts. METTL3 deficiency reduces N⁶-methyladenosine (m⁶A) deposition on TCF7L2, Smad2, and Smad3 transcripts, impairing YTHDF2-mediated recognition and degradation, leading to their abnormal stabilization and subsequent protein accumulation. Elevated TCF7L2 partners with Smad2/3 to form a transcriptional complex that directly binds to the FN1 and COL1A1 promoters, driving their expression and extracellular matrix deposition. Exogenous modulation of METTL3 expression either mimics or reverses the TGF-β1-induced fibrotic phenotypes both in vitro and in vivo. Our findings reveal a mechanism through which environmental factors influence pterygium progression by modulating the formation of fibrotic transcriptional complexes via epitranscriptomic regulation. These insights offer potential avenues for treating fibrosis by targeting the epitranscriptome or specific transcriptional complexes.
- Pterygium,
- METTL3,
- YTHDF2,
- TCF7L2–Smad2/3,
- Transcriptional complexes

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References

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