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Galectin-3-integrin α5β1 phase separation disrupted by advanced glycation end-products impairs diabetic wound healing in rodents

Author

Listed:
  • Zhongyu Zhang

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Zhengde Zhao

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Xiuyi Huang

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Lifang Zhou

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Xin Jiang

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Haoliang Wu

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Chenshu Liu

    (The Fifth Affiliated Hospital of Sun Yat-sen University)

  • Kan Huang

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Jielu Wen

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Yunchong Liu

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Michelle C. Miller

    (University of Minnesota)

  • Zihan Zhao

    (Northeast Normal University)

  • Zhen He

    (Northeast Normal University)

  • Yuxin Wang

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Siyu Liu

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Lijin Huang

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Lining Yuan

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Renli Zeng

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Zhipeng Cen

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Anning Chen

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

  • Yanbo Chen

    (Sun Yat-sen University)

  • Gang Zeng

    (Sun Yat-sen University)

  • Wenzhou Liu

    (Sun Yat-sen University)

  • Xiaosi Hong

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases)

  • Meng Ren

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases)

  • Li Yan

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases)

  • Yang Zhang

    (Sun Yat-sen University)

  • Dongxian Guan

    (Nanjing University)

  • Xiaoyu Tian

    (Shatin NT)

  • Weikang Cai

    (New York Institute of Technology, College of Osteopathic Medicine)

  • Guihua Tai

    (Northeast Normal University)

  • Kevin H. Mayo

    (University of Minnesota)

  • Yifa Zhou

    (Northeast Normal University)

  • Zilun Li

    (The First Affiliated Hospital of Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Sifan Chen

    (Sun Yat-sen University
    Guangdong Clinical Research Center for Metabolic Diseases
    Sun Yat-sen University
    Sun Yat-sen Memorial Hospital)

Abstract

Diabetic foot ulcers are severe diabetic complications, and promoting impaired angiogenesis is essential for wound healing. Pro-angiogenic galectin-3 is elevated in diabetic serum and promotes systemic insulin resistance that may impair wound healing. However, the exact role of galectin-3 in the regulation of diabetic wound healing remains unclear. Here, we demonstrate that galectin-3 promotes skin wound healing and angiogenesis via binding to its receptor integrin α5β1, and enhances downstream focal adhesion kinase phosphorylation by forming a liquid-liquid phase separation with integrin α5β1. Under diabetic conditions, aberrant accumulated advanced glycation end-products bind to galectin-3, blocking its interaction with integrin α5β1 and impairing angiogenesis. Topical treatment of recombinant galectin-3 in hydrogels promotes diabetic wound healing in rodents without causing systemic insulin resistance and synergizes with insulin. This study clarifies the binding of galectin-3 to integrin α5β1, instead of advanced glycation end-products, forming phase separation to promote angiogenesis and diabetic wound healing, laying the foundation for local galectin-3 therapy to treat diabetic foot ulcers.

Suggested Citation

  • Zhongyu Zhang & Zhengde Zhao & Xiuyi Huang & Lifang Zhou & Xin Jiang & Haoliang Wu & Chenshu Liu & Kan Huang & Jielu Wen & Yunchong Liu & Michelle C. Miller & Zihan Zhao & Zhen He & Yuxin Wang & Siyu , 2025. "Galectin-3-integrin α5β1 phase separation disrupted by advanced glycation end-products impairs diabetic wound healing in rodents," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62320-w
    DOI: 10.1038/s41467-025-62320-w
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    References listed on IDEAS

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    1. Beatrice Dyring-Andersen & Marianne Bengtson Løvendorf & Fabian Coscia & Alberto Santos & Line Bruun Pilgaard Møller & Ana R. Colaço & Lili Niu & Michael Bzorek & Sophia Doll & Jørgen Lock Andersen & , 2020. "Spatially and cell-type resolved quantitative proteomic atlas of healthy human skin," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Antonio Filareto & Sarah Parker & Radbod Darabi & Luciene Borges & Michelina Iacovino & Tory Schaaf & Timothy Mayerhofer & Jeffrey S. Chamberlain & James M. Ervasti & R. Scott McIvor & Michael Kyba & , 2013. "An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells," Nature Communications, Nature, vol. 4(1), pages 1-9, June.
    3. Linda Lorenz & Jennifer Axnick & Tobias Buschmann & Carina Henning & Sofia Urner & Shentong Fang & Harri Nurmi & Nicole Eichhorst & Richard Holtmeier & Kálmán Bódis & Jong-Hee Hwang & Karsten Müssig &, 2018. "Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival," Nature, Nature, vol. 562(7725), pages 128-132, October.
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