Uncovering SOD3 and GPX4 as new targets of Benzo[α]pyrene-induced hepatotoxicity through Metabolomics and Chemical Proteomics

Wang, Yanwei1; Zhao, Jiahui2,3; Xu, Yipeng4; Tao, Cimin1; Tong, Jie5; Luo, Yingjie1,6; Chen, Yong1,6; Liu, Xuesong1,6; Xu, Tengfei1,6

2023-11-01

10.1016/j.redox.2023.102930

REDOX BIOLOGY   影响因子和分区

2213-2317

Benzo[alpha]pyrene (Bap) is recognized as a ubiquitous environmental pollutant among the polycyclic aromatic hydrocarbons (PAHs) class. Previous studies have shown that the hepatotoxicity of Bap is mainly caused by its metabolites, although it remains unclear whether Bap itself induces such damage. This study integrated metabolomics and chemical proteomics approaches to comprehensively identify the potential target proteins affected by Bap in liver cells. The results from the metabolomics showed that the significant changed metabolites were related with cellular redox homeostasis. CEllular Thermal Shift Assay (CETSA) showed that Bap induced protein thermal displacement of superoxide dismutase 3 (SOD3) and glutathione peroxidase 4 (GPX4), which are closely related to oxidative homeostasis. Further validation through in vitro CETSA and drug affinity response target stability (DARTS) revealed that Bap directly affected the stability of SOD3 and GPX4 proteins. The binding affinities of Bap to the potential target proteins were further evaluated using molecular docking, while the isothermal titration calorimetry (ITC) interaction measurements indicated nanomolar-level Kd values. Importantly, we found that Bap weakened the antioxidant capacity by destroying the activities of SOD3 and GPX4, which provided a new understanding of the mechanism of hepatotoxicity induced by Bap. Moreover, our provided workflow integrating metabolomics and label-free chemical proteomics, can be regarded as a practical way to identify the targets and inter-mechanisms for the various environmental compounds.

Benzo[ alpha]pyrene Superoxide dismutase 3 Glutathione peroxidase 4 Metabolomics Chemical proteomics

SCI

英语

其他

National Natural Science Foundation of China[82204584] ; Chinese Pharmacopoeia Commission[2022Y12] ; Fundamental Research Funds from Shenzhen Science and Technology Innovation Commission[RCBS20210609104424065]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:001109121000001

ELSEVIER

Web of Science

1.Zhejiang Univ, Coll Pharmaceut Sci, Key Lab Adv Drug Delivery Syst Zhejiang Prov, Hangzhou 310058, Zhejiang, Peoples R China
2.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Geriatr,Clin Med Coll 2, Shenzhen 518020, Guangdong, Peoples R China
3.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Shenzhen Clin Res Ctr Geriatr,Cl, Shenzhen 518020, Guangdong, Peoples R China
4.Zhejiang Canc Hosp, Dept Urol, Hangzhou 310022, Zhejiang, Peoples R China
5.Yale Sch Med, Dept Radiol & Biomed Imaging, PET Ctr, New Haven, CT 06520 USA
6.Cangnan Cty Qiushi Innovat Res Inst Tradit Chinese, Wenzhou 325899, Zhejiang, Peoples R China

Wang, Yanwei,Zhao, Jiahui,Xu, Yipeng,et al. Uncovering SOD3 and GPX4 as new targets of Benzo[α]pyrene-induced hepatotoxicity through Metabolomics and Chemical Proteomics[J]. REDOX BIOLOGY,2023,67.

Wang, Yanwei.,Zhao, Jiahui.,Xu, Yipeng.,Tao, Cimin.,Tong, Jie.,...&Xu, Tengfei.(2023).Uncovering SOD3 and GPX4 as new targets of Benzo[α]pyrene-induced hepatotoxicity through Metabolomics and Chemical Proteomics.REDOX BIOLOGY,67.

Wang, Yanwei,et al."Uncovering SOD3 and GPX4 as new targets of Benzo[α]pyrene-induced hepatotoxicity through Metabolomics and Chemical Proteomics".REDOX BIOLOGY 67(2023).