Abstract
Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 μM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1−/− mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.
Highlight
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Ferroptosis is responsible for doxorubicin-induced cardiotoxicity.
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Bach1 expression is prominently increased by doxorubicin.
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Bach1 knockdown alleviates doxorubicin-induced cardiotoxicity.
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Bach1 promotes ferroptosis of cardiomyocytes through downregulation of HO-1.
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Data will be made available from the corresponding author on reasonable request.
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Funding
This work was supported by grants from Joint Fund of Shandong Natural Science Foundation (No. ZR2022LSW025), Shandong Natural Science Foundation (No. ZR2021MH400) and Shandong Natural Science Foundation (No. ZR2019MH125).
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All authors contributed to the study conception and design. Haiyan Lou planned experiments and interpreted data. Yanwei Wang performed most of the experiments and analyzed data. Jingru Qiu and Nan Zhang participated in the animal experiment. Hua Yan and Shixuan Gao participated in the cell experiment. Ning Xu participated in the experiment design and data interpretation. Cuiyan Wang participated in the experiment design and manuscript revision. Yanwei Wang wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final article.
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Wang, Y., Qiu, J., Yan, H. et al. The Bach1/HO-1 pathway regulates oxidative stress and contributes to ferroptosis in doxorubicin-induced cardiomyopathy in H9c2 cells and mice. Arch Toxicol (2024). https://doi.org/10.1007/s00204-024-03697-3
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DOI: https://doi.org/10.1007/s00204-024-03697-3