YTHDF3 suppresses declines in corneal epithelial wound healing through upregulating the Wnt/β-catenin signaling pathway and THBS2 expression in diabetic corneas

• Published in: International journal of biological macromolecules 2025-01, Vol.285, p.138267, Article 138267
• Main Authors: Wang, Jingrao, Zhu, Rui, Dong, Yueyan, Feng, Jiaoyang, Gao, Jingfan, Wang, Shu, Lin, Jia, Li, Yulin, Du, Weijie, Jin, Xin, Zhang, Hong
• Format: Article
• Language: English
• Subjects: cornea; Corneal epithelial wound healing; Diabetes; domain; epithelium; family; glycation; humans; m6A; microarray technology; RNA; RNA translation; THBS2; therapeutics; YTHDF3
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.138267

Corneal complications associated with diabetes are gradually receiving attention because of the large number of patients with diabetes. The current treatment for diabetic corneal lesions relies on symptomatic relief, which has uncertain efficacy. Exploring the mechanisms underlying delayed corneal epithelial healing in diabetes is of great significance for the treatment of this disease. N6-methyladenosine (m6A), the most common modification of RNA, plays a key role in a range of diseases. Nevertheless, the role and mechanisms underlying m6A regulation in diabetic corneal epithelial wound healing have not yet been elucidated. Here, we found that thrombospondin 2 (THBS2) was downregulated in the corneas of diabetic mice using m6A-mRNA and lncRNA epitranscriptomic microarrays. Overexpression of THBS2 promoted the proliferation and migration of human corneal epithelial cells (HCECs) by activating the Wnt/β-catenin signaling pathway. Enforced THBS2 expression promoted corneal epithelial wound healing in diabetic mice. Moreover, we found that the m6A reader protein YTH domain family protein 3 (YTHDF3) was downregulated at the mRNA and protein levels in the corneas of both diabetic mice and HCECs treated with glycation end products. YTHDF3 knockdown delayed corneal epithelial wound healing in diabetic mice. Mechanistically, YTHDF3 promoted THBS2 translation by recognizing m6A sites in the coding region of THBS2. Collectively, our findings indicate that THBS2 plays a vital role in regulating corneal epithelial wound healing, and targeting the YTHDF3/THBS2 axis could offer a potential therapeutic strategy for treating delayed corneal epithelial wound healing.