PDF(Pubmed)
Abstract：
Cisplatin is a widely used antineoplastic drug for treating various types of cancers. However, it can cause severe side effects, such as bilateral and irreversible hearing loss, which significantly impacts quality of life. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of cisplatin-induced ototoxicity. Here, we investigated the effects of nuciferine, a natural active ingredient isolated from lotus species, on the ferroptosis of cochlear hair cells. Firstly, our results demonstrated that nuciferine can protect hair cells against RSL3-induced and cisplatin-induced damage. Secondly, nuciferine treatment reduced ferrous iron (Fe2+) overload in cochlear hair cells via inhibiting NCOA4-mediated ferritinophagy. Inhibition of ferritinophagy by knocking down Ncoa4 alleviated cisplatin-induced ototoxicity. Importantly, nuciferine treatment mitigated cochlear hair cell loss and damage to ribbon synapse, and improved mouse hearing function in an acute cisplatin-induced hearing loss model. Our findings highlight the role of NCOA4-mediated ferritinophagy in the pathogenesis of cisplatin-induced ototoxicity and provide evidence for nuciferine as a promising protective agent for treating cisplatin-induced hearing loss.
摘要：
顺铂是一种广泛使用的抗肿瘤药物，用于治疗各种类型的癌症。然而,会引起严重的副作用,如双边和不可逆转的听力损失，显著影响生活质量。Ferroptosis,一种依赖铁的程序性细胞死亡形式，与顺铂诱导的耳毒性的发病机理有关。这里,我们调查了荷叶碱的影响，从莲花物种中分离出的天然活性成分，耳蜗毛细胞的铁性凋亡。首先,我们的结果表明,荷叶碱可以保护毛细胞免受RSL3和顺铂诱导的损伤.其次,荷叶碱处理可通过抑制NCOA4介导的自噬减少耳蜗毛细胞中的亚铁（Fe2）过载。通过敲低Ncoa4抑制铁素吞噬减轻顺铂诱导的耳毒性。重要的是,荷叶碱治疗减轻耳蜗毛细胞损失和对带状突触的损害，在急性顺铂诱导的听力损失模型中改善小鼠的听力功能。我们的发现强调了NCOA4介导的铁细胞自噬在顺铂诱导的耳毒性发病机制中的作用，并为nucificine作为治疗顺铂诱导的听力损失的有希望的保护剂提供了证据。
