2. Academic Validation
  3. Dulaglutide accelerates diabetic wound healing by suppressing Nrf2-dependent ferroptosis in diabetic mice

Dulaglutide accelerates diabetic wound healing by suppressing Nrf2-dependent ferroptosis in diabetic mice

  • Peptides. 2025 Mar:185:171366. doi: 10.1016/j.peptides.2025.171366.
Liuqing Xi 1,  Juan Du 1,  Yan Lu 1,  Wen Xue 2,  Yuxuan Xia 2,  Tingxu Chen 1,  Yang Xiao 2,  Nuo Xu 2,  Yansheng Wang 2,  Jianfang Gao 3,  Wenyi Li 4,  Shan Huang 5
Affiliations

Affiliations

  • 1 Department of Endocrinology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 College of Biological Science and Medical Engineering, Donghua University, Shanghai, China.
  • 3 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jfgao@shsmu.edu.cn.
  • 4 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: liwenyimail@hotmail.com.
  • 5 Department of Endocrinology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: hs1147@126.com.
PMID: 39954860 DOI: 10.1016/j.peptides.2025.171366
Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently utilized to treat type 2 diabetes mellitus (T2DM). Several GLP-1RAs (Exendin-4 and liraglutide) have been shown to accelerate diabetic wound healing. The major aim of the study was to investigate the roles of dulaglutide in wound healing in diabetic mice and identify the underlying mechanism involved. Round-shape, full-thickness wounds were created on the backs of db/db diabetic mice. Subsequently, dulaglutide was delivered via subcutaneous injections surrounding the wound's perimeter, and the wound closure rates were monitored. In vitro, keratinocytes were treated with dulaglutide under high glucose (HG) conditions, and cell viability was assessed by cell counting kit-8 (CCK-8) and EdU assays. The roles of dulaglutide in Ferroptosis were assessed by measuring the levels of Fe2 + and oxidative stress, as well as the expression of Ferroptosis markers. The results demonstrated that dulaglutide treatment increased the expression of vascular endothelial growth factor (VEGF) and the proliferation marker Ki67, thereby accelerating wound healing in diabetic mice. In vitro, dulaglutide promoted HaCaT cell proliferation and migration under HG conditions. Exposure of HaCaT cells to HG resulted in Ferroptosis in vivo and in vitro, as evidenced by the significant increase in Fe2+, Reactive Oxygen Species (ROS), and malondialdehyde (MDA) levels and the decrease in glutathione (GSH) and superoxide dismutase (SOD) levels. All these effects were reversed by dulaglutide. Mechanistically, dulaglutide activated NFE2-related factor 2 (Nrf2) signaling under HG conditions, which increased Glutathione Peroxidase (Gpx4) and solute carrier family 7-member 11 (Slc7a11) expression, thereby inhibiting Ferroptosis. In summary, these results demonstrate dulaglutide as a promising agent for treating diabetic wounds by regulating Nrf2-dependent Ferroptosis.

Keywords

GLP-1RAs; Nrf2; diabetic wound healing; dulaglutide; ferroptosis.

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