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Abstract：
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.
摘要：
多柔比星（DOX）介导的心脏毒性可加剧肿瘤患者的死亡率，但相关的药物治疗措施相对有限。Ferroptosis最近被认为是DOX诱导的心脏毒性的主要机制。Idebenone,一种新型的铁凋亡抑制剂，是一种广泛使用的临床药物。然而,其在DOX诱导的心脏毒性中的作用和病理机制尚不清楚。在这项研究中,我们证明了艾地苯醌对DOX诱导的心脏毒性的影响，并阐明了其潜在的机制。单次腹膜内注射DOX(15mg/kg)以建立DOX诱导的心脏毒性。结果表明，艾地苯醌由于具有调节急性DOX诱导的Fe2和ROS超负荷的能力，可明显减轻DOX诱导的心功能不全。导致铁性凋亡。CESTA和BLI进一步揭示了艾地苯醌的抗铁凋亡作用是由FSP1介导的。有趣的是,在DOX存在下，艾地苯醌增加FSP1蛋白水平，但不影响Fsp1mRNA水平。艾地苯醌可以在K355与FSP1蛋白形成稳定的氢键，这可能影响其与泛素的缔合。结果证实艾地苯醌通过抑制其泛素化降解来稳定FSP1蛋白水平。总之,这项研究证明艾地苯醌通过调节FSP1抑制铁凋亡来减轻DOX诱导的心脏毒性，使其成为接受DOX治疗的患者的潜在临床药物。
