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Copper Exposure Induced Chicken Hepatotoxicity: Involvement of Ferroptosis Mediated by Lipid Peroxidation, Ferritinophagy, and Inhibition of FSP1-CoQ10 and Nrf2/SLC7A11/GPX4 Axis

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Abstract

Copper (Cu) is one of the most significant trace elements in the body, but it is also a widespread environmental toxicant health. Ferroptosis is a newly identified programmed cell death, which involves various heavy metal–induced organ toxicity. Nevertheless, the role of ferroptosis in Cu-induced hepatotoxicity remains poorly understood. In this study, we found that 330 mg/kg Cu could disrupt the liver structure and cause characteristic morphological changes in mitochondria associated with ferroptosis. Additionally, Cu treatment increased MDA (malondialdehyde) and LPO (lipid peroxide) production while reducing GSH (reduced glutathione) content and GCL (glutamate cysteine ligase) activity. However, it is noticeable that there were no appreciable differences in liver iron content and key indicators of iron metabolism. Meanwhile, our further investigation found that 330 mg/kg Cu-exposure changed multiple ferroptosis-related indicators in chicken livers, including inhibition of the expression of SLC7A11, GPX4, FSP1, and COQ10B, whereas enhances the levels of ACLS4, LPCAT3, and LOXHD1. Furthermore, the changes in the expression of NCOA4, TXNIP, and Nrf2/Keap1 signaling pathway–related genes and proteins also further confirmed 330 mg/kg Cu exposure-induced ferroptosis. In conclusion, our results indicated that ferroptosis may play essential roles in Cu overload–induced liver damage, which offered new insights into the pathogenesis of Cu-induced hepatotoxicity.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 32072930 and 31572585).

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Authors and Affiliations

  1. College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China

    Gaolong Zhong, Yuanxu Li, Feiyang Ma, Yihui Huo, Jianzhao Liao, Qingyue Han, Lianmei Hu & Zhaoxin Tang

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Contributions

Conceptualization: Gaolong Zhong; methodology: Gaolong Zhong, Jianzhao Liao, and Feiyang Ma; formal analysis and investigation: Gaolong Zhong, Yuanxu Li, Feiyang Ma, and Yihui Huo; writing—original draft preparation: Gaolong Zhong; writing—review and editing: Qingyue Han and Lianmei Hu; funding acquisition: Zhaoxin Tang; resources: Zhaoxin Tang; supervision: Zhaoxin Tang.

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Correspondence to Zhaoxin Tang.

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Zhong, G., Li, Y., Ma, F. et al. Copper Exposure Induced Chicken Hepatotoxicity: Involvement of Ferroptosis Mediated by Lipid Peroxidation, Ferritinophagy, and Inhibition of FSP1-CoQ10 and Nrf2/SLC7A11/GPX4 Axis. Biol Trace Elem Res 202, 1711–1721 (2024). https://doi.org/10.1007/s12011-023-03773-2

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