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

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

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.
PMID: 40775187 DOI: 10.1038/s41467-025-62320-w
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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