Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics

Liu, Xueying1,4,5; Zhang, Qian1,2,3; Wang, Peili1,10; Peng, Xin1,9; An, Yehai1,2,3; Chen, Junhui1; Huang, Jingnan1; Qin, Shuanglin11; He, Hengkai1; Hao, Mingjing1; Tian, Jiahang2,3; Yi, Letai1,6; Lei, Ming1,12; Luo, Piao1,2,3,11; Wang, Jigang1,2,3,7,8,9; Zhang, Xinzhou1,4,5

2024

10.7150/ijbs.91751

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES   影响因子和分区

1449-2288

Celastrol (Cel), derived from the traditional herb Tripterygium wilfordii Hook. f., has anti-inflammatory, anti-tumor, and immunoregulatory activities. Renal dysfunction, including acute renal failure, has been reported in patients following the administration of Cel-relative medications. However, the functional mechanism of nephrotoxicity caused by Cel is unknown. This study featured combined use of activity-based protein profiling and metabolomics analysis to distinguish the targets of the nephrotoxic effects of Cel. Results suggest that Cel may bind directly to several critical enzymes participating in metabolism and mitochondrial functions. These enzymes include voltage-dependent anion-selective channel protein 1 (essential for maintaining mitochondrial configurational and functional stability), pyruvate carboxylase (involved in sugar isomerization and the tricarboxylic acid cycle), fatty acid synthase (related to beta-oxidation of fatty acids), and pyruvate kinase M2 (associated with aerobic respiration). Proteomics and metabolomics analysis confirmed that Cel-targeted proteins disrupt some metabolic biosynthetic processes and promote mitochondrial dysfunction. Ultimately, Cel aggravated kidney cell apoptosis. These cumulative results deliver an insight into the potential mechanisms of Cel-caused nephrotoxicity. They may also facilitate development of antagonistic drugs to mitigate the harmful effects of Cel on the kidneys and improve its clinical applications.

celastrol nephrotoxicity chemical proteomics metabolomics mitochondrial dysfunction apoptosis

SCI

英语

第一 ; 通讯

National Key Research and Development Program of China[2020YFA0908000] ; Shenzhen Medical Research Fund[B2302051] ; National Natural Science Foundation of China[82074098] ; Shenzhen Governmental Sustainable Development Fund[KCXFZ20201221173612034] ; Shenzhen key Laboratory of Kidney Diseases[ZDSYS201504301616234] ; Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties[SZGSP001] ; Shenzhen Funda-mental Research Foundation[JCYJ20210324113001 005] ; Medical research Fund of Shenzhen Medical Academy of Research and Translation[C2301004]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:001309543000002

IVYSPRING INT PUBL

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Sch Med,Guangdong Prov Clin Res Ctr Geriatr,Shenzh, Shenzhen 518020, Guangdong, Peoples R China
2.Southern Med Univ, Sch Tradit Chinese Med, Guangzhou 510515, Peoples R China
3.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
4.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen Key Lab Kidney Dis, Shenzhen 518020, Peoples R China
5.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
6.Inner Mongolia Med Univ, Hohhot 010107, Peoples R China
7.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
8.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
9.Zhejiang Chinese Med Univ, Ningbo Municipal Hosp TCM, Affiliated Hosp, Ningbo 310060, Peoples R China
10.China Acad Chinese Med Sci, Xiyuan Hosp, Natl Clin Res Ctr Chinese Med Cardiol, Beijing 100091, Peoples R China
11.Hunan Univ Chinese Med, Natl Engn Res Ctr Personalized Diagnost & Therapeu, TCM Precis Med Res Dept, FuRong Lab, Changsha 410007, Hunan, Peoples R China
12.Guangzhou Eighth Peoples Hosp, Dept Nephrol, Guangzhou 510440, Guangdong, Peoples R China

Liu, Xueying,Zhang, Qian,Wang, Peili,et al. Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics[J]. INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,2024,20(12).

Liu, Xueying.,Zhang, Qian.,Wang, Peili.,Peng, Xin.,An, Yehai.,...&Zhang, Xinzhou.(2024).Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics.INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,20(12).

Liu, Xueying,et al."Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics".INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 20.12(2024).