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

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 Liu, Lijin Huang, Lining Yuan, Renli Zeng, Zhipeng Cen, Anning Chen, Yanbo Chen, Gang Zeng, Wenzhou Liu, Xiaosi Hong, Meng Ren, Li Yan, Yang Zhang, Dongxian Guan, Xiaoyu Tian, Weikang Cai, Guihua Tai, Kevin H. Mayo (), Yifa Zhou (), Zilun Li () and Sifan Chen ()
Additional contact information
Zhongyu Zhang: Sun Yat-sen University
Zhengde Zhao: The First Affiliated Hospital of Sun Yat-sen University
Xiuyi Huang: The First Affiliated Hospital of Sun Yat-sen University
Lifang Zhou: Sun Yat-sen University
Xin Jiang: Sun Yat-sen University
Haoliang Wu: 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
Jielu Wen: Sun Yat-sen University
Yunchong Liu: 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
Siyu Liu: Sun Yat-sen University
Lijin Huang: Sun Yat-sen University
Lining Yuan: Sun Yat-sen University
Renli Zeng: Sun Yat-sen University
Zhipeng Cen: Sun Yat-sen University
Anning Chen: Sun Yat-sen University
Yanbo Chen: Sun Yat-sen University
Gang Zeng: Sun Yat-sen University
Wenzhou Liu: Sun Yat-sen University
Xiaosi Hong: Sun Yat-sen University
Meng Ren: Sun Yat-sen University
Li Yan: Sun Yat-sen University
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
Sifan Chen: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62320-w

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