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

  • Nat Commun. 2025 Aug 7;16(1):7287. doi: 10.1038/s41467-025-62320-w.
Zhongyu Zhang  #  1  2  3  4  5  6  7 Zhengde Zhao  #  8  9 Xiuyi Huang  #  8  9 Lifang Zhou  #  1  2  3  4 Xin Jiang  #  1  2  3  4 Haoliang Wu  8  9 Chenshu Liu  10 Kan Huang  8  9 Jielu Wen  1  2  3  4 Yunchong Liu  8  9 Michelle C Miller  11 Zihan Zhao  5 Zhen He  5 Yuxin Wang  1  2  3  4 Siyu Liu  1  2  3  4 Lijin Huang  1  2  3  4 Lining Yuan  1  2  3  4 Renli Zeng  1  2  3  4 Zhipeng Cen  1  2  3  4 Anning Chen  1  2  3  4 Yanbo Chen  12 Gang Zeng  12 Wenzhou Liu  12 Xiaosi Hong  1  2 Meng Ren  1  2 Li Yan  1  2 Yang Zhang  13 Dongxian Guan  14 Xiaoyu Tian  15 Weikang Cai  16 Guihua Tai  5 Kevin H Mayo  17 Yifa Zhou  18 Zilun Li  19  20 Sifan Chen  21  22  23  24  25
Affiliations
  • 1. Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Guangdong Clinical Research Center for Metabolic Diseases, Guangzhou, China.
  • 3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4. Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, China.
  • 5. Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, China.
  • 6. Clinical Research Center, Hainan Hospital, Guangdong Provincial Hospital of Chinese Medicine, Haikou, Hainan, China.
  • 7. Clinical Research Center, Affiliated Chinese Medicine Hospital of Hainan Medical University, Haikou, Hainan, China.
  • 8. Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 9. National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 10. Center for Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
  • 11. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • 12. Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 13. School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.
  • 14. Institute of Modern Biology, Nanjing University, Nanjing, China.
  • 15. School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, China.
  • 16. Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY, USA.
  • 17. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, USA. [email protected].
  • 18. Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, China. [email protected].
  • 19. Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 20. National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 21. Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 22. Guangdong Clinical Research Center for Metabolic Diseases, Guangzhou, China. [email protected].
  • 23. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 24. Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, China. [email protected].
  • 25. Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China. [email protected].
  • # Contributed equally.
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.

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