Diabetic wound healing, including diabetic foot ulcer (DFU), is a serious complication of diabetes. Considering the complexity of DFU development, the identification of a factor that mediates multiple pathogeneses is important for treatment. In this study, we found that CXXC-type zinc finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of the Wnt/β-catenin pathway and its target genes involved in wound healing and angiogenesis in the wound tissues of DFU patients and diabetes-induced model mice. KY19334, a small molecule that activates the Wnt/β-catenin pathway by inhibiting the CXXC5-Dvl interaction, accelerated wound healing in diabetic mice. The enhancement of diabetic wound healing could be achieved by restoring the suppressed Wnt/β-catenin signaling and subsequently inducing its target genes. Moreover, KY19334 induced angiogenesis in hindlimb ischemia model mice. Overall, these findings revealed that restorative activation of Wnt/β-catenin signaling by inhibiting the function of cytosolic CXXC5 could be a therapeutic approach for treating DFUs.
© 2023. The Author(s).