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.

阿霉素（DOX）是最常用的化疗药物之一，属于蒽环类药物。然而，蒽环类药物的心脏毒性作用限制了其临床应用。最近的研究表明铁死亡是DOX诱导的心肌病（DIC）的主要潜在发病机制。 BTB-and-CNC 同源 1 (Bach1) 在铁死亡的调节中发挥关键作用。然而，Bach1 在 DIC 中的机制作用仍不清楚。因此，本研究旨在利用体内 DIC 小鼠（DOX 累积剂量为 20 mg/kg）和体外 DOX 处理的 H9c2 心肌细胞（1 μM）研究 Bach1 在 DOX 诱导的心脏毒性中的潜在机制作用。我们的结果显示，DOX 处理的小鼠心脏组织和 DOX 处理的心肌细胞中 Bach1 的表达显着上调。然而，Bach1 ^−/−小鼠在DOX治疗后表现出脂质过氧化减少和心肌病减轻。在体内和体外模型中，Bach1 敲低可防止 DOX 诱导的铁死亡。 Ferrostatin-1 (Fer-1) 是一种有效的铁死亡抑制剂，可显着减轻 DOX 引起的心脏损伤。然而，用血红素加氧酶-1 (HO-1) 的选择性抑制剂锌原卟啉 (ZnPP) 预处理可逆转 Bach1 敲低的心脏保护作用。综上所述，这些发现表明 Bach1 通过抑制 HO-1 的表达来促进氧化应激和铁死亡。因此，Bach1可能成为预防和早期干预DOX诱导的心脏毒性的有前途的新治疗靶点。