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. mayox001@umn.edu.
  • 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. zhouyf383@nenu.edu.cn.
  • 19 Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. lizilun@mail.sysu.edu.cn.
  • 20 National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. lizilun@mail.sysu.edu.cn.
  • 21 Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. chensf26@mail.sysu.edu.cn.
  • 22 Guangdong Clinical Research Center for Metabolic Diseases, Guangzhou, China. chensf26@mail.sysu.edu.cn.
  • 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. chensf26@mail.sysu.edu.cn.
  • 24 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, China. chensf26@mail.sysu.edu.cn.
  • 25 Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China. chensf26@mail.sysu.edu.cn.
  • # 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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