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

作　　者：Hongliang Qiu Sihui Huang Yuting Liu Libo Liu Fengming Guo Yingying Guo Dan Li Xianfeng Cen Yajie Chen Meng Zhang Yan Che Man Xu Qizhu Tang 

机构地区：[1]Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan 430060,China [2]Hubei Key Laboratory of Metabolic and Chronic Diseases,Wuhan 430060,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2581-2597,共17页药学学报（英文版）

基　　金：supported by the following grants:the Regional Innovation and Development Joint Fund of the National Natural Science Foundation of China(No.U22A20269);the National Key R&D Program of China(No.2018YFC1311300);the National Natural Science Foundation of China(Nos.82200262 and 82000229).

摘　　要：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 Fe^(2+)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.

关 键 词：IDEBENONE DOX-induced cardiotoxicity Ferroptosis FSP1 UBIQUITINATION Lipid peroxidation Iron overload Clinical translation 

分 类 号：R965[医药卫生—药理学]