MMP-9 responsive hydrogel promotes diabetic wound healing by suppressing ferroptosis of endothelial cells

Chuanlu Lin; Yiqiang Hu; Ze Lin; Longyu Du; Yixin Hu; Lizhi Ouyang; Xudong Xie; Peng Cheng; Jiewen Liao; Li Lu; Ruiyin Zeng; Ping Xia; Zhiyong Hou; Guohui Liu; Hankun Hu

Bioactive Materials (Jan 2025)

MMP-9 responsive hydrogel promotes diabetic wound healing by suppressing ferroptosis of endothelial cells

Chuanlu Lin,
Yiqiang Hu,
Ze Lin,
Longyu Du,
Yixin Hu,
Lizhi Ouyang,
Xudong Xie,
Peng Cheng,
Jiewen Liao,
Li Lu,
Ruiyin Zeng,
Ping Xia,
Zhiyong Hou,
Guohui Liu,
Hankun Hu

Affiliations

Chuanlu Lin: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Yiqiang Hu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Ze Lin: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Longyu Du: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Yixin Hu: School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
Lizhi Ouyang: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Xudong Xie: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Peng Cheng: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Jiewen Liao: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Li Lu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Ruiyin Zeng: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
Ping Xia: Department of Orthopaedics, Wuhan Fourth Hospital (Puai Hospital), Wuhan, China; Corresponding author. Department of Orthopaedics, Wuhan Fourth Hospital (Puai Hospital), Wuhan, 430033, China.
Zhiyong Hou: Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, China; Key Laboratory of Orthopaedic Biomechanics of Hebei Province, Shijiazhuang, China; Corresponding authors. Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, China.
Guohui Liu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China; Corresponding author. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Hankun Hu: Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Micro-explore Innovative Pharmaceutical Research Co., Ltd, Wuhan, Hubei, 430074, China; Suzhou Organ-on-a-Chip System Science and Technology Co., Ltd, Suzhou, Jiangsu, 215000, China; Corresponding author. Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.

Journal volume & issue: Vol. 43
pp. 240 – 254

Abstract

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Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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