Inhibiting the cytosolic function of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair

  • Exp Mol Med. 2023 Aug;55(8):1770-1782. doi: 10.1038/s12276-023-01064-3.
Eunhwan Kim  1 ,  Seol Hwa Seo  1 ,  Yumi Hwang  1 ,  Yeong Chan Ryu  1 ,  Heejene Kim  1 ,  Kyoung-Mi Lee  2 ,  Jin Woo Lee  2  3 ,  Kwang Hwan Park  4 ,  Kang-Yell Choi  5  6
Affiliations
  • 1. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
  • 2. Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, 03722, South Korea.
  • 3. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea.
  • 4. Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, 03722, South Korea. [email protected].
  • 5. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea. [email protected].
  • 6. CK Regeon Inc, Engineering Research Park, 50 Yonsei Ro, Seodaemun-Gu, Seoul, 03722, South Korea. [email protected].
PMID: 37524876 DOI: 10.1038/s12276-023-01064-3
Abstract

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.

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