2. Academic Validation
  3. CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell activation

CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell activation

  • Cell Commun Signal. 2025 Feb 25;23(1):108. doi: 10.1186/s12964-025-02097-z.
Yutong Chen # 1,  Xiaofeng Ding # 2,  Zhouji Ma # 3 4,  Shuai Shao # 5,  Heyan Huang 6,  Yumeng Huang 7,  Beizhi Wang 8,  Hao Zhang 5,  Qian Tan 9 10
Affiliations

Affiliations

  • 1 Department of Burns and Plastic Surgery, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. 985881572@qq.com.
  • 2 Department of Dermatologic Surgery, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3 Department of Burn and Plastic Surgery, Gulou Clinical Medical College of Nanjing Medical University, Nanjing, China.
  • 4 Department of Plastic and Aesthetic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • 5 Department of Burns and Plastic Surgery, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
  • 6 Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
  • 7 Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China.
  • 8 Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 9 Department of Burns and Plastic Surgery, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. smmutanqian@sina.com.
  • 10 Department of Burns and Plastic Surgery, Anqing Shihua Hospital, Nanjing Drum Tower Hospital Group, Anqing, China. smmutanqian@sina.com.
  • # Contributed equally.
PMID: 40001144 DOI: 10.1186/s12964-025-02097-z
Abstract

Background: Extracellular matrix (ECM) and angiogenesis are critical controls of wound regeneration, and their dysfunction delays diabetes recovery. CXXC5 belongs to the CXXC protein family that can regulate the function of human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs); However, awareness of its functional role remains limited.

Methods: Mice were divided into control (CON), diabetic (DM), diabetic + KY19382 (DM + KY19382), and diabetic + vehicle (DM + Vehicle) groups. HDFs and HUVECs were stimulated under different CXXC5 conditions and mice were treated with KY19382, followed by the application of assays including Western blotting (WB), immunofluorescence (IF) and quantitative reverse transcription-PCR (qRT-PCR) to assess wound healing and molecular signaling.

Results: Mice in DM had fewer blood vessels, a slower wound healing rate, and more disrupted collagen than CON. Application of KY19382 improved these conditions, which promoted fibroblast activation and vascularization in high glucose environments and DM. Mechanistically, blocking CXXC5 promotes Wnt/β-catenin-mediated stabilization by reducing the binding of the deterrent factor CTBP1 to β-catenin, which induces dermal fibroblast activation and facilitates HUVECs tube formation and migration via VEGFA/VEGFR2/KDR/Flk-1 and NFκB signaling pathways. KY19382 promotes HUVECs activation by blocking CTBP1 transcription to activate the NFκB signaling pathway, thus wound re-vascularization.

Conclusion: CXXC5 is an essential regulatory factor of wound healing and a prospective therapeutic target for treating chronic wound damage in diabetes.

Keywords

Angiogenesis; CXXC5; Diabetes; Fibroblast; Wound healing.

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