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Yongqiang Xiao,1,* Dayuan Xu,1,* Hongyuan Song,2,* Futing Shu,1 Pei Wei,3 Xiaolan Yang,3 Chenjian Zhong,3 Xiaohong Wang,4 Werner EG Müller,4 YongJun Zheng,1 Shichu Xiao,1,* Zhaofan Xia11Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China; 2Department of Ophthalmology, Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China; 3Department of Burns Surgery, Union Hospital, Fujian Medical University, Fuzhou 350001, People's Republic of China; 4Erc Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz 55128, Germany*These authors contributed equally to this workBackground: Less apoptosis and excessive growth of fibroblasts contribute to the progression of hypertrophic scar formation. Cuprous oxide nanoparticles (CONPs) could have not only inhibited tumor by inducing apoptosis and inhibiting proliferation of tumor cells, but also promoted wound healing. The objective of this study was to further explore the therapeutic effects of CONPs on hypertrophic scar formation in vivo and in vitro.Methods: In vivo, a rabbit ear scar model was established on New Zealand albino rabbits. Six full-thickness and circular wounds (10 mm diameter) were made to each ear. Following complete re-epithelization observed on postoperative day 14, an intralesional injection of CONPs or 5% glucose solution was conducted to the wounds. The photo and ultrasonography of each wound were taken every week and scars were harvested on day 35 for further histomorphometric analysis. In vitro, the role of CONPs in human hypertrophic scar fibroblasts (HSFs) apoptosis and proliferation were evaluated by Tunnel assay, Annexin V/PI staining, cell cycle analysis, and EdU proliferation assay. The endocytosis of CONPs by fibroblasts were detected through transmission electron microscopy (TEM) and the mitochondrial membrane potential and ROS production were also detected.Results: In vivo, intralesional injections of CONPs could significantly improve the scar appearance and collagen arrangement, and decreased scar elevation index (SEI). In vitro, CONPs could prominently inhibit proliferation and induce apoptosis in HSFs in a concentration-dependent manner. In addition, CONPs could be endocytosed into mitochondria，damage the mitochondrial membrane potential and increase ROS production.Conclusion: CONPs possessed the therapeutic potential in the treatment of hypertrophic scar by inhibiting HSFs proliferation and inducing HSFs apoptosis.Keywords: CONPs, hypertrophic scar, apoptosis, proliferation, mitochondria