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.
摘要：
阿霉素（DOX）是蒽环类最常用的化疗药物之一。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和CNC同源性1（Bach1）在铁凋亡的调节中起关键作用。然而,Bach1在DIC中的作用机制尚不清楚.因此,这项研究旨在研究Bach1在DIC小鼠体内（累积剂量为20mg/kg的DOX）和体外DOX处理的H9c2心肌细胞（1μM）中DOX诱导的心脏毒性中的潜在机制作用。我们的结果表明，在DOX处理的小鼠和DOX处理的心肌细胞的心脏组织中，Bach1的表达明显上调。然而,Bach1-/-小鼠在DOX治疗后表现出降低的脂质过氧化和较不严重的心肌病。在体内和体外模型中,Bach1敲低保护免受DOX诱导的铁凋亡。Ferrostatin-1(Fer-1),一种有效的铁凋亡抑制剂，显著减轻DOX诱导的心脏损伤。然而,用锌原卟啉（ZnPP）预处理可以逆转Bach1敲低的心脏保护作用，血红素加氧酶-1（HO-1）的选择性抑制剂。一起来看,这些发现表明Bach1通过抑制HO-1的表达促进氧化应激和铁凋亡。因此,Bach1可能是预防和早期干预DOX引起的心脏毒性的有希望的新治疗靶标。
