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

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

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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 car-diotoxicity are still unclear.In this study,we demonstrated the effects of idebenone on DOX-induced car-diotoxicity 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 signifi-cantly 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 regu-lation of FSP1,making it a potential clinical drug for patients receiving DOX treatment.

IdebenoneDOX-induced cardiotoxicityFerroptosisFSP1UbiquitinationLipid peroxidationIron overloadClinical translation

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

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Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan 430060,China

Hubei Key Laboratory of Metabolic and Chronic Diseases,Wuhan 430060,China

Regional Innovation and Development Joint Fund of the National Natural Science Foundation of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

U22A202692018YFC13113008220026282000229

2024

10.1016/j.apsb.2024.03.015

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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