顺铂对杀死肿瘤细胞非常有效。然而，其中一个副作用——耳毒性限制了顺铂的临床应用。顺铂诱导的耳毒性机制尚未完全阐明。SIRT3是一种去乙酰化蛋白，主要位于线粒体中，调节细胞中的多种生理过程。SIRT3在顺铂诱导的毛细胞损伤中的作用尚未发现。本研究使用暴露于5μM顺铂的原代培养耳蜗解剖组织以及暴露于10μM顺铂的OC-1细胞，建立了体外顺铂诱导耳毒性模型。我们发现，与顺铂相结合时，二甲双胍（75μM）显著上调了SIRT3的表达，并减轻了顺铂引起的毛细胞凋亡。我们调节了SIRT3的表达，以探索SIRT3在顺铂诱导的听觉毛细胞损伤中的作用。SIRT3的过表达促进了听觉毛细胞的生存并减轻了听觉毛细胞的凋亡。相反，SIRT3的敲下破坏了二甲双胍的保护作用，并加重了顺铂的损伤。此外，我们发现SIRT3的保护作用可能是通过调节GLUT4转位并挽救顺铂引起的受损葡萄糖摄取而实现的。我们的研究证实了上调SIRT3可能对抗顺铂引起的耳毒性，并为顺铂引起的耳毒性研究提供了新的视角。 ©2023年。作者（们）在Springer-Verlag GmbH Germany 的独家许可下，属于Springer Nature的一部分。

Cisplatin is highly effective for killing tumor cells. However, as one of its side effects, ototoxicity limits the clinical application of cisplatin. The mechanisms of cisplatin-induced ototoxicity have not been fully clarified yet. SIRT3 is a deacetylated protein mainly located in mitochondria, which regulates a variety of physiological processes in cells. The role of SIRT3 in cisplatin-induced hair cell injury has not been founded. In this study, primary cultured cochlear explants exposed to 5 μM cisplatin, as well as OC-1 cells exposed to 10 μM cisplatin, were used to establish models of cisplatin-induced ototoxicity in vitro. We found that when combined with cisplatin, metformin (75 μM) significantly up-regulated the expression of SIRT3 and alleviated cisplatin-induced apoptosis of hair cells. We regulated the expression of SIRT3 to explore the role of SIRT3 in cisplatin-induced auditory hair cell injury. Overexpression of SIRT3 promoted the survival of auditory hair cells and alleviated the apoptosis of auditory hair cells. In contrast, knockdown of SIRT3 impaired the protective effect of metformin and exacerbated cisplatin injury. In addition, we found that the protective effect of SIRT3 may be achieved by regulating GLUT4 translocation and rescuing impaired glucose uptake caused by cisplatin. Our study confirmed that upregulation of SIRT3 may antagonize cisplatin-induced ototoxicity, and provided a new perspective for the study of cisplatin-induced ototoxicity.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.