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Targeting senescent HDF with the USP7 inhibitor P5091 to enhance DFU wound healing through the p53 pathway

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机构： [1]Institute of Burns, Wuhan Third Hospital (Tongren Hospital of WuHan University), Wuhan 430060, China. [2]School of Medicine, Jianghan University, Wuhan, 430056, China. [3]Marine Biomedical Research Institute of Qingdao, Key Laboratory of Marine Drugs Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.

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关键词： Diabetic foot ulcer Deubiquitin-specific protease 7 (USP7) Senescence Wound healing p53 pathway

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The objective of this study was to examine the potential of USP7 as a target for senolytic therapy and to investigate the molecular mechanism by which its inhibitor selectively induced apoptosis in senescent HDF and enhanced DFU wound healing.Clinical samples of DFU were collected to detect the expression of USP7 and aging-related proteins using immunohistochemistry and Western blot. In addition, β-galactosidase staining, qPCR, flow cytometry, ROS and MMP kits, and Western blot were used to analyze the biological functions of P5091 on senescence, cycle, and apoptosis. RNAseq was employed to further analyze the molecular mechanism of P5091. Finally, the DFU rat model was established to evaluate the effect of P5091 on wound healing.The expression of USP7 and p21 were increased in DFU clinical samples. After treatment with d-glucose (30 mM, 7 days), β-galactosidase staining was deepened, proliferation rate decreased. USP7 inhibitors (P5091) could reduce the release of SASP factors, activate the production of ROS, and reduce MMP. In addition, it induced apoptosis and selectively clears senescent cells through the p53 signaling pathway. Finally, P5091 can improve diabetic wound healing in rats.This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells. This provides a new senolytics target and experimental basis for promoting DFU wound healing.Copyright © 2024 Elsevier Inc. All rights reserved.

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出版当年[2023]版：

大类 | 3 区生物学

小类 | 3 区生物物理 4 区生化与分子生物学

最新[2023]版：

大类 | 3 区生物学

小类 | 3 区生物物理 4 区生化与分子生物学

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出版当年[2022]版：

Q2 BIOPHYSICS Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

最新[2023]版：

Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Q3 BIOPHYSICS

影响因子： 2.5 最新[2023版] 2.7 最新五年平均 3.1 出版当年[2022版] 3.2 出版当年五年平均 3.322 出版前一年[2021版] 2.5 出版后一年[2023版]

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第一作者机构： [1]Institute of Burns, Wuhan Third Hospital (Tongren Hospital of WuHan University), Wuhan 430060, China.

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