2. Academic Validation
  3. The Bach1/HO-1 pathway regulates oxidative stress and contributes to ferroptosis in doxorubicin-induced cardiomyopathy in H9c2 cells and mice

The Bach1/HO-1 pathway regulates oxidative stress and contributes to ferroptosis in doxorubicin-induced cardiomyopathy in H9c2 cells and mice

  • Arch Toxicol. 2024 Apr 4. doi: 10.1007/s00204-024-03697-3.
Yanwei Wang 1 2,  Jingru Qiu 1,  Hua Yan 3,  Nan Zhang 4,  Shixuan Gao 5,  Ning Xu 1,  Cuiyan Wang 2,  Haiyan Lou 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
  • 2 Department of Radiology, Shandong Provincial Hospital, No. 324 Jingwu Road, Jinan, 250021, Shandong, China.
  • 3 Department of Gastroenterology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China.
  • 4 Research Center of Translational Medicine, Breast Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China.
  • 5 Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China. louhaiyan@sdu.edu.cn.
PMID: 38573338 DOI: 10.1007/s00204-024-03697-3
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.

Keywords

Bach1; Cardiotoxicity; Doxorubicin; Ferroptosis; HO-1.

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