复旦大学Jun Ren等研究人员合作发现，亚细亚酸通过促进FPN介导的铁排出和抑制铁死亡改善多柔比星诱导的心脏毒性。相关论文于2024年8月14日在线发表在《中国药理学报》杂志上。

研究人员表示，多柔比星（DOX）是癌症治疗中常用的化疗药物，但伴随显著的心脏毒性。铁死亡被认为与DOX诱导的心脏毒性（DIC）的发病机制和治疗有关。亚细亚酸（AA）是一种来源于中药积雪草的五环三萜，具有抗氧化、抗炎和抗凋亡活性。

研究人员探讨了AA对DOX诱导的铁死亡和心脏毒性的保护作用及其潜在机制。通过每周一次（5 mg/kg，腹腔注射）给予DOX，为期4周，建立了慢性DIC小鼠模型。与DOX处理同时，小鼠还接受了AA（25 mg/kg每天，口服）治疗。在治疗结束时，评估了心脏功能和分离心肌细胞的机械性能。结果表明，AA治疗保持了心脏功能，显著减少了心脏损伤，并改善了DIC小鼠的心肌收缩功能。

AA的有益效果与DOX诱导的铁死亡抑制相关，体内外实验均显示AA能通过增加FPN介导的铁排出来减轻DOX诱导的铁积累，且这一过程依赖于Nrf2。AA上调了Nrf2的表达并促进了Nrf2在DOX处理的HL-1细胞中的核转位。此外，Nrf2抑制剂ML385（30 mg/kg每天，腹腔注射）在AA前30分钟注射，导致AA对DOX诱导的心脏功能障碍和铁死亡的保护作用丧失。这些数据表明，AA通过促进FPN介导的铁排出来抑制铁过载和铁死亡，提示其在DIC治疗中的潜在治疗价值。

附：英文原文

Title: Asiatic acid ameliorates doxorubicin-induced cardiotoxicity by promoting FPN-mediated iron export and inhibiting ferroptosis

Author: Wu, Lin, Wang, Li-tao, Du, Yu-xin, Zhang, Ying-mei, Ren, Jun

Issue&Volume: 2024-08-14

Abstract: 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 (5mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25mg·kg1·d1, 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 (30mg·kg-1·d-1, i.p.) administrated 30min 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.

DOI: 10.1038/s41401-024-01367-9

Source: https://www.nature.com/articles/s41401-024-01367-9