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.
- 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.
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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