Epigenetics and diabetic wound healing: Wilms tumor 1-associated protein as a therapeutic target

In this editorial, we highlight the study by Xiao et al. Despite progress in the management of diabetic foot ulcers (DFUs), impaired wound healing remains a significant clinical challenge. Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing, with particular emphasis on DNA and RNA methylation pathways. This editorial discusses the findings of Xiao et al, who identified the Wilms tumor 1-associated protein (WTAP) - DNA methyltransferase 1 (DNMT1) axis as a pivotal regulator of endothelial dysfunction in DFUs. WTAP, a regulatory subunit of N6-methyladenosine (m6A) methyltransferase, is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification. This contributes to impaired angiogenesis, reduced cell viability, and delayed wound closure. WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model. Furthermore, DNMT1 overexpression abrogated the benefits of WTAP suppression, confirming its downstream effector role. Thus, targeting the WTAP-DNMT1 axis provides a new avenue for DFU management. Moreover, epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.