Pou4f3 plays an important role in the development of hair cells in the inner ear sensory epithelia. Autophagy is related to the auditory damage. However, the role and mechanism of Pou4f3 on drug-induced ototoxicity are incompletely understood. Hence, this study aimed to explore the effects of Pou4f3 on the apoptosis of cochlear hair cells (CHCs) and to explore whether autophagy was involved in this process. The cisplatin was used to produce a loss of CHCs to create a murine model of deafness. The AAV vectors were delivered into the scala media through the lateral wall. Compared with the control mice, the cisplatin-treated mice exhibited significantly enhanced apoptosis and autophagy in the cochleae, accompanied by a notably decreased Pou4f3 levels. Both mutation and knockdown of Pou4f3 promoted the apoptosis- and autophagy-related protein levels, and enhanced the cisplatin-induced levels of apoptosis- and autophagy-related proteins. Furthermore, the autophagy activator rapamycin promoted the apoptosis and autophagy in the cochlea. In addition, the autophagy inhibitor 3-MA overturned the promoting effect of Pou4f3 knockdown on the apoptosis and autophagy. Collectively, in cisplatin-induced deafness mice, the Pou4f3 gene mutation facilitated apoptosis of cochlear hair cells, at least partially, through inducing autophagy.

中文翻译：

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Pou4f3基因突变促进顺铂诱导的耳聋小鼠耳蜗毛细胞自噬和凋亡。

Pou4f3在内耳感觉上皮细胞的毛细胞发育中起重要作用。自噬与听觉损伤有关。但是，Pou4f3在药物诱导的耳毒性中的作用和机制尚不完全清楚。因此，本研究旨在探讨Pou4f3对耳蜗毛细胞（CHC）凋亡的影响，并探讨自噬是否参与该过程。顺铂用于产生CHC的损失，从而建立小鼠耳聋模型。AAV载体通过侧壁传递到scala介质中。与对照小鼠相比，顺铂处理的小鼠耳蜗细胞凋亡和自噬显着增强，同时Pou4f3水平明显降低。Pou4f3的突变和敲低均可促进细胞凋亡和自噬相关蛋白的水平，并增强了顺铂诱导的凋亡相关蛋白和自噬相关蛋白的水平。此外，自噬激活剂雷帕霉素促进了耳蜗的凋亡和自噬。另外，自噬抑制剂3-MA推翻了Pou4f3敲低对细胞凋亡和自噬的促进作用。集体地，在顺铂诱导的耳聋小鼠中，Pou4f3基因突变通过诱导自噬至少部分地促进了耳蜗毛细胞的凋亡。