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

被引：21

作者：

Lin, Chuanlu ^{[1
,2
]}

Hu, Yiqiang ^{[1
,2
]}

Lin, Ze ^{[1
,2
]}

Du, Longyu ^{[1
,2
]}

Hu, Yixin ^{[3
]}

Ouyang, Lizhi ^{[1
,2
]}

Xie, Xudong ^{[1
,2
]}

Cheng, Peng ^{[1
,2
]}

Liao, Jiewen ^{[1
,2
]}

Lu, Li ^{[1
,2
]}

Zeng, Ruiyin ^{[1
,2
]}

Xia, Ping ^{[4
]}

Hou, Zhiyong ^{[5
,6
]}

Liu, Guohui ^{[1
,2
]}

Hu, Hankun ^{[7
,8
,9
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Orthoped, Wuhan 430022, Peoples R China

[2] Hubei Prov Key Lab Oral & Maxillofacial Dev & Rege, Wuhan 430022, Peoples R China

[3] Wuhan Univ, Sch Pharmaceut Sci, Wuhan 430071, Peoples R China

[4] Wuhan Fourth Hosp, Puai Hosp, Dept Orthopaed, Wuhan, Peoples R China

[5] Hebei Med Univ, Dept Orthopaed Surg, Hosp 3, Shijiazhuang, Peoples R China

[6] Key Lab Orthopaed Biomech Hebei Prov, Shijiazhuang, Peoples R China

[7] Wuhan Univ, Zhongnan Hosp, Sch Pharmaceut Sci, Dept Pharm, Wuhan 430071, Peoples R China

[8] Hubei Microexplore Innovat Pharmaceut Res Co Ltd, Wuhan 430074, Hubei, Peoples R China

[9] Suzhou Organ On a Chip Syst Sci & Technol Co Ltd, Suzhou 215000, Jiangsu, Peoples R China

来源：

BIOACTIVE MATERIALS | 2025年 / 43卷

基金：

美国国家科学基金会;

关键词：

Ferroptosis; TRPA1; Diabetes mellitus; Wound healing; Hydrogel; RECEPTOR POTENTIAL CHANNELS; CINNAMALDEHYDE; EXPRESSION; TARGET;

D O I：

10.1016/j.bioactmat.2024.09.006

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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.

引用

页码：240 / 254

页数：15

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