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

Acta Pharmacologica Sinica volume 46, pages 81–95 (2025)Cite this article

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 (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.

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Fig. 1: AA protects against onset and progression of DIC.
Fig. 2: AA attenuates DOX-induced cardiomyocyte mechanical anomalies.
Fig. 3: AA inhibits DOX-induced cardiac ferroptosis in vivo.
Fig. 4: AA inhibits DOX-induced cardiomyocyte ferroptosis in vitro.
Fig. 5: AA reduces DOX-induced iron accumulation by promoting FPN-mediated iron export.
Fig. 6: Anti-ferroptotic effects of AA are FPN-dependent in DOX-treated cardiomyocytes.
Fig. 7: Nrf2 is involved in the regulation of AA-mediated iron homeostasis.
Fig. 8: Protection of AA against DIC and ferroptosis is Nrf2-dependent.
Fig. 9: Proposed working model for cardioprotective effects of AA against DIC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82130011, 92249301, and RFIS82250710173).

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  1. These authors contributed equally: Lin Wu, Li-tao Wang, Yu-xin Du.

Authors and Affiliations

  1. Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China

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

  2. National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China

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

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LW and JR designed the study. LW, LTW, and YXD performed the study and analyzed the data. LW drafted the manuscript; YMZ and JR supervised the study and edited the manuscript.

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Correspondence to Ying-mei Zhang or Jun Ren.

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Wu, L., Wang, Lt., Du, Yx. et al. Asiatic acid ameliorates doxorubicin-induced cardiotoxicity by promoting FPN-mediated iron export and inhibiting ferroptosis. Acta Pharmacol Sin 46, 81–95 (2025). https://doi.org/10.1038/s41401-024-01367-9

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