Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis

• Published in: Acta pharmaceutica Sinica. B 2024-06, Vol.14 (6), p.2581-2597
• Main Authors: Qiu, Hongliang, Huang, Sihui, Liu, Yuting, Liu, Libo, Guo, Fengming, Guo, Yingying, Li, Dan, Cen, Xianfeng, Chen, Yajie, Zhang, Meng, Che, Yan, Xu, Man, Tang, Qizhu
• Format: Article
• Language: English
• Subjects: Clinical translation; DOX-induced cardiotoxicity; Ferroptosis; FSP1; Idebenone; Iron overload; Lipid peroxidation; Original; Ubiquitination
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2024.03.015

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment. Idebenone protects against DOX-induced cardiotoxicity by inhibiting ferroptosis via stabilizing FSP1 protein, providing a clinical transformation drug with promising therapeutic potential. [Display omitted]