This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

目的:探讨LLY-283通过蛋白质精氨酸甲基转移酶(protein arginine methyltransferase 5,PRMT5)对头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)增殖和转移生物学行为的影响.方法:通过TCGA数据库、实时荧光定量PCR和免疫印迹实验检测PRMT5在HNSCC组织、细胞系中表达水平;利用慢病毒技术构建PRMT5敲低稳转细胞株,分析PRMT5对HNSCC细胞生物学行为影响,药物杀伤实验观察LLY-283在细胞系中IC50变化;细胞实验和裸鼠移植瘤实验进一步检测LLY-283通过PRMT5对HNSCC生物学作用.结果:PRMT5在HNSCC组织和细胞系中高表达,促进HNSCC增殖和转移能力,降低药物LLY-283的IC50值.LLY-283可通过PRMT5显著降低HNSCC增殖和转移能力、体内裸鼠移植瘤体积和Ki-67表达量.结论:LLY-283可能通过抑制PRMT5和Ki-67表达,降低HNSCC增殖、转移和裸鼠移植瘤形成能力,发挥抗肿瘤作用.