European journal of pharmacology · 2026
Isoginkgetin ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via the SIRT1/NRF2 pathway.
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Mo Hongwei, Su Han, Zhuang Zhenyu, Guan Junjie, Zhang Xuwei, Chen Deshu, Guo Runze, Chen Xiangzhou, Zhou Bin, Chen Liheng, Zhong Chongbin, Yang Pingzhen
Аннотация
BACKGROUND: Doxorubicin-induced cardiotoxicity (DIC) poses a substantial threat to the prognosis and survival of cancer patients. Ferroptosis, mediated in part by suppression of the SIRT1/NRF2 pathway, has been identified as a critical mechanism underlying DIC. Isoginkgetin (IGK), a naturally occurring biflavonoid with recognized cardioprotective potential, has yet to be evaluated for its efficacy to mitigate DIC. Furthermore, whether the cardioprotective effects of IGK are mediated through the modulation of SIRT1/NRF2-dependent ferroptosis remains unexplored. Accordingly, this study was designed to investigate whether IGK attenuates DIC by activating the SIRT1/NRF2 signaling axis to suppress ferroptosis.
METHODS: In vitro, injury of AC16 cells was assessed using CCK-8 assay, LDH release measurement, and PI/Hoechst 33342 staining. In vivo, cardiac function and myocardial injury in mice were evaluated by echocardiography and serum myocardial injury biomarker analysis. Myocardial atrophy was assessed by hematoxylin and eosin (H&E) and wheat germ agglutinin (WGA) staining. Additionally, we measured several ferroptosis-related biomarkers, including malondialdehyde (MDA) content, PTGS2 mRNA expression, glutathione (GSH) level, and lipid peroxidation levels.
RESULTS: IGK exerted protective effects against DIC in both in vivo and in vitro models. This cardioprotection was associated with the suppression of doxorubicin (DOX)-induced ferroptosis. Mechanistically, IGK attenuated the DOX-induced downregulation of SIRT1 and suppressed ferroptosis by activating the SIRT1/NRF2 signaling pathway. Notably, the cardioprotective effects of IGK against ferroptosis and DIC were partially reversed upon siRNA-mediated silencing of SIRT1.
CONCLUSIONS: IGK mitigated DIC by activating the SIRT1/NRF2 signaling pathway, highlighting its potential as a therapeutic candidate for DIC.
METHODS: In vitro, injury of AC16 cells was assessed using CCK-8 assay, LDH release measurement, and PI/Hoechst 33342 staining. In vivo, cardiac function and myocardial injury in mice were evaluated by echocardiography and serum myocardial injury biomarker analysis. Myocardial atrophy was assessed by hematoxylin and eosin (H&E) and wheat germ agglutinin (WGA) staining. Additionally, we measured several ferroptosis-related biomarkers, including malondialdehyde (MDA) content, PTGS2 mRNA expression, glutathione (GSH) level, and lipid peroxidation levels.
RESULTS: IGK exerted protective effects against DIC in both in vivo and in vitro models. This cardioprotection was associated with the suppression of doxorubicin (DOX)-induced ferroptosis. Mechanistically, IGK attenuated the DOX-induced downregulation of SIRT1 and suppressed ferroptosis by activating the SIRT1/NRF2 signaling pathway. Notably, the cardioprotective effects of IGK against ferroptosis and DIC were partially reversed upon siRNA-mediated silencing of SIRT1.
CONCLUSIONS: IGK mitigated DIC by activating the SIRT1/NRF2 signaling pathway, highlighting its potential as a therapeutic candidate for DIC.