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

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 i...

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Main Authors: 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, Sifan Chen
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-62320-w
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Summary: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.
ISSN:2041-1723

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