阿霉素（DOX）是癌症治疗中常见的化疗药物，具有明显的心脏毒性。铁死亡与 DOX 诱导的心脏毒性 (DIC) 的发病机制和治疗有关。积雪草酸 (AA) 是一种来自中药积雪草的五环三萜，具有抗氧化、抗炎和抗细胞凋亡活性。在这项研究中，我们研究了 AA 对 DOX 诱导的铁死亡和心脏毒性的有益作用及其潜在机制。通过每周一次用 DOX（5 mg/kg，腹膜内注射）攻击小鼠建立慢性 DIC 模型，持续 4 周。在DOX损伤的同时，给小鼠施用AA（例如25mg·kg-1·d-1）。在治疗结束时评估离体心肌细胞的心脏功能和机械特性。我们发现，给予 DIC 小鼠 AA 可以保护心脏功能，显着减少心脏损伤，并改善心肌细胞收缩功能。 AA 的有益作用与在体内和体外抑制 DOX 诱导的铁死亡有因果关系。我们发现，AA 通过增加 FPN 介导的铁输出（以 Nrf2 依赖性方式）来减弱 DOX 诱导的 HL-1 细胞中的铁积累。在 DOX 处理的 HL-1 细胞中，AA 上调 Nrf2 表达并促进 Nrf2 核转位。此外，在 DIC 小鼠中，在 AA 30 分钟前给予 Nrf2 抑制剂 ML385（30mg·kg-1·d-1，腹腔注射）可以消除 AA 对 DOX 诱导的心功能障碍和铁死亡的益处。我们的数据支持 AA 促进 FPN 介导的铁输出，从而抑制 DIC 中的铁过载和铁死亡，表明其在治疗 DIC 方面的治疗潜力。© 2024。作者，经上海药物研究所独家许可，中文中国科学院、中国药理学会.

Doxorubicin (DOX), a common chemotherapeutic agent in cancer therapy, is accompanied by pronounced cardiotoxicity. Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity (DIC). Asiatic acid (AA), a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica, displays antioxidant, anti-inflammatory, and antiapoptotic activities. In this study, we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms. A chronic DIC model was established by challenging mice with DOX (5 mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25 mg·kg-1·d-1, i.g.). Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment. We showed that AA administration preserved cardiac function, significantly reduced cardiac injury, and improved cardiomyocyte contractile function in DIC mice. The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro. We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export, in a Nrf2-dependent manner. AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells. Moreover, AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385 (30 mg·kg-1·d-1, i.p.) administrated 30 min before AA in DIC mice. Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC, suggesting its therapeutic potential in the treatment of DIC.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.