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; Sifan Chen

doi:10.1038/s41467-025-62320-w

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, Sifan Chen

Producción científica: Article › revisión exhaustiva

19 Citas (Scopus)

Resumen

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.

Idioma original	English
Número de artículo	7287
Publicación	Nature Communications
Volumen	16
N.º	1
DOI	https://doi.org/10.1038/s41467-025-62320-w
Estado	Published - dic 2025

Nota bibliográfica

Publisher Copyright:
© The Author(s) 2025.

Financiación

This work is supported by grants from The National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (No. 82222014 to S.C.); Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507600 to S.C.); The National Natural Science Foundation of China (No. 32271185 to S.C.); National Key R&D Program of China (2023YFA1800700 to S.C.); Guangdong Clinical Research Center for Metabolic Diseases (No. 2020B1111170009 to L.Y.) and Guangzhou key laboratory for Metabolic Diseases (No. 202102100004 to L.Y.); Guangdong Science and Technology Department (2023B1212060013 to S.C.); Guangdong Basic and Applied Basic Research Foundation (2024A1515010318 to Z.L.); Guangzhou Science and Technology Program Key Projects (2024B03J1254 to Z.L.); National Natural Science Foundation of China (No. 3217110198 to G.T.); Hainan Provincial Natural Science Foundation Youth Fund project (No. 824QN392 to ZY.Z.); Hainan Provincial Nanhai New Star Science and Technology Innovation Platform Project (No. NHXXRCXM202349 to ZY.Z.). In silico virtual docking simulation was performed using GRAMM Web ( https://gramm.compbio.ku.edu/ ).

Financiadores	Número del financiador
Guangzhou Key Laboratory for Metabolic Diseases	202102100004
National Natural Science Foundation of China (NSFC)	32271185
Basic and Applied Basic Research Foundation of Guangdong Province	2024A1515010318
National Outstanding Youth Science Fund Project of National Natural Science Foundation of China	82222014, 2023ZD0507600
National Key Basic Research and Development Program of China	2023YFA1800700
Guangdong Provincial Department of Science and Technology and Guangzhou Science Technology and Innovation Commission	2023B1212060013
Hainan Provincial Nanhai New Star Science and Technology Innovation Platform Project	NHXXRCXM202349
Guangdong Clinical Research Center for Metabolic Diseases	2020B1111170009
Natural Science Foundation of Hainan Province	824QN392
Guangzhou Municipal Science and Technology Program key projects	3217110198, 2024B03J1254

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

Acceder al documento

10.1038/s41467-025-62320-w

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Zhang, Z., Zhao, Z., Huang, X., Zhou, L., Jiang, X., Wu, H., Liu, C., Huang, K., Wen, J., Liu, Y., Miller, M. C., Zhao, Z., He, Z., Wang, Y., Liu, S., Huang, L., Yuan, L., Zeng, R., Cen, Z., ... Chen, S. (2025). Galectin-3-integrin α5β1 phase separation disrupted by advanced glycation end-products impairs diabetic wound healing in rodents. Nature Communications, 16(1), Artículo 7287. https://doi.org/10.1038/s41467-025-62320-w

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title = "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 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.",

author = "Zhongyu Zhang and Zhengde Zhao and Xiuyi Huang and Lifang Zhou and Xin Jiang and Haoliang Wu and Chenshu Liu and Kan Huang and Jielu Wen and Yunchong Liu and Miller, \{Michelle C.\} and Zihan Zhao and Zhen He and Yuxin Wang and Siyu Liu and Lijin Huang and Lining Yuan and Renli Zeng and Zhipeng Cen and Anning Chen and Yanbo Chen and Gang Zeng and Wenzhou Liu and Xiaosi Hong and Meng Ren and Li Yan and Yang Zhang and Dongxian Guan and Xiaoyu Tian and Weikang Cai and Guihua Tai and Mayo, \{Kevin H.\} and Yifa Zhou and Zilun Li and Sifan Chen",

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Zhang, Z, Zhao, Z, Huang, X, Zhou, L, Jiang, X, Wu, H, Liu, C, Huang, K, Wen, J, Liu, Y, Miller, MC, Zhao, Z, He, Z, Wang, Y, Liu, S, Huang, L, Yuan, L, Zeng, R, Cen, Z, Chen, A, Chen, Y, Zeng, G, Liu, W, Hong, X, Ren, M, Yan, L, Zhang, Y, Guan, D, Tian, X, Cai, W, Tai, G, Mayo, KH, Zhou, Y, Li, Z & Chen, S 2025, 'Galectin-3-integrin α5β1 phase separation disrupted by advanced glycation end-products impairs diabetic wound healing in rodents', Nature Communications, vol. 16, n.º 1, 7287. https://doi.org/10.1038/s41467-025-62320-w

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AU - Zhang, Zhongyu

AU - Zhao, Zhengde

AU - Huang, Xiuyi

AU - Zhou, Lifang

AU - Jiang, Xin

AU - Wu, Haoliang

AU - Liu, Chenshu

AU - Huang, Kan

AU - Wen, Jielu

AU - Liu, Yunchong

AU - Miller, Michelle C.

AU - Zhao, Zihan

AU - He, Zhen

AU - Wang, Yuxin

AU - Liu, Siyu

AU - Huang, Lijin

AU - Yuan, Lining

AU - Zeng, Renli

AU - Cen, Zhipeng

AU - Chen, Anning

AU - Chen, Yanbo

AU - Zeng, Gang

AU - Liu, Wenzhou

AU - Hong, Xiaosi

AU - Ren, Meng

AU - Yan, Li

AU - Zhang, Yang

AU - Guan, Dongxian

AU - Tian, Xiaoyu

AU - Cai, Weikang

AU - Tai, Guihua

AU - Mayo, Kevin H.

AU - Zhou, Yifa

AU - Li, Zilun

AU - Chen, Sifan

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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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JO - Nature Communications

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ER -

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

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

Acceder al documento

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