ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Integrative and Regenerative Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1614967
This article is part of the Research TopicInnovative Approaches for Wound TreatmentView all 12 articles
Narirutin treatment accelerates the process of diabetic wound repair via regulating phenotype switching of macrophages through affecting metabolic reprogramming
Provisionally accepted
- 1Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 2Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei Province, China
- 3Qingdao Women and Children's Hospital, Qingdao, Shandong Province, China
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Diabetic foot ulcer (DFU) is one of the most common complications of diabetes with substantial morbidity and mortality. Narirutin (Nar), a bioactive phytochemical derived from the citrus peel, has been suggested to possess anti-inflammatory abilities. Whereas, the involvement of Nar in the DFU development is poorly understood. We found that high glucose treatment significant elevated the contents of TNF-α and IL-1β and lactate and reduced the levels of TGF-β1 and IL-4 and α-ketoglutarate in bone marrow derived macrophages (BMDMs). Then, Nar intervention effectively induced BMDMs repolarization from M1 to M2 state and the molecular mechanism was ascribed to drugelicited activation of AMPK, which in turn increased the expression of downstream Mfn2, thereby enhancing the activity of oxidative phosphorylation and GATA3 cascade activation and disrupting the progress of glycolysis and NF-κB axis activation. Subsequently, we discovered that Nar injection effectively enhanced the healing rate of skin wounds in diabetic mice. Histological analysis showed that Nar dose-dependently induced dermis growth and collagen deposition in the wound area. Via activating AMPK/Mfn2 axis, Nar inhibited the activity of glycolysis and enhanced the extent of oxidative phosphorylation, accompanied by inflammation repression and angiogenesis promotion in the damaged tissue. Our study discovered that macrophages repolarization to M2 phenotype was required for Nar-induced promotive effects on diabetic wound repair by regulating reprogramming of glucose metabolism via mediating AMPK/Mfn2 pathway.
Keywords: Diabetic foot ulcer, Narirutin, macrophage, metabolic reprogramming, AMPK, Inflammation
Received: 20 Apr 2025; Accepted: 26 May 2025.
Copyright: © 2025 Lu, Liu, Wang, Zhou, Lu, Zhang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Li Lu, Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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