Lonicerin promotes wound healing in diabetic rats by enhancing blood vessel regeneration through Sirt1-mediated autophagy

Zhen Lin1,2, Lu-yao Li3, Lu Chen1, Chen Jin4, Yue Li1, Lan Yang1, Chang-zhou Li1, Cai-yu Qi1, Yu-yang Gan1, Jia-rui Zhang1, Piao Wang1, Li-bin Ni5, Gao-feng Wang1,2
1 Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou 510515, China
2 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21210, USA
3 College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
4 Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325702, China
5 Department of Orthopaedic Surgery, Zhejiang Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou 310014, China
Correspondence to: Li-bin Ni:, Gao-feng Wang:,
DOI: 10.1038/s41401-023-01193-5
Received: 8 July 2023
Accepted: 8 November 2023
Advance online: 8 December 2023


Among the numerous complications of diabetes mellitus, diabetic wounds seriously affect patients’ quality of life and result in considerable psychological distress. Promoting blood vessel regeneration in wounds is a crucial step in wound healing. Lonicerin (LCR), a bioactive compound found in plants of the Lonicera japonica species and other honeysuckle plants, exhibits anti- inflammatory and antioxidant activities, and it recently has been found to alleviate ulcerative colitis by enhancing autophagy. In this study we investigated the efficacy of LCR in treatment of diabetic wounds and the underlying mechanisms. By comparing the single-cell transcriptomic data from healing and non-healing states in diabetic foot ulcers (DFU) of 5 patients, we found that autophagy and SIRT signaling activation played a crucial role in mitigating inflammation and oxidative stress, and promoting cell survival in wound healing processes. In TBHP-treated human umbilical vein endothelial cells (HUVECs), we showed that LCR alleviated cell apoptosis, and enhanced the cell viability, migration and angiogenesis. Furthermore, we demonstrated that LCR treatment dose-dependently promoted autophagy in TBHP-treated HUVECs by upregulating Sirt1 expression, and exerted its anti- apoptotic effect through the Sirt1-autophagy axis. Knockdown of Sirt1 significantly decreased the level of autophagy, and mitigated the anti-apoptotic effect of LCR. In a STZ-induced diabetic rat model, administration of LCR significantly promoted wound healing, which was significantly attenuated by Sirt1 knockdown. This study highlights the potential of LCR as a therapeutic agent for the treatment of diabetic wounds and provides insights into the molecular mechanisms underlying its effects.
Keywords: diabetic wounds; wound healing; lonicerin; oxidative stress; angiogenesis; autophagy; Sirt1

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