Zheng Zhiwei, Nan Benyu, Liu Chang, Tang Dongmei, Li Wen, Zhao Liping, Nie Guohui, He Yingzi
ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, Shanghai, 200031, China.
Department of Otorhinolaryngology-Head and Neck Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
J Pharm Anal. 2023 Jun;13(6):590-602. doi: 10.1016/j.jpha.2023.04.014. Epub 2023 Apr 26.
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 gene, thus activating the expression of . 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.
本研究旨在评估抑制蛋白质精氨酸甲基转移酶5（PRMT5）在顺铂诱导的听力损失中的治疗潜力。使用免疫组织化学、凋亡检测和听性脑干反应来确定PRMT5抑制对顺铂诱导的听觉损伤的影响。在HEI-OC1细胞系中，使用RNA测序和靶向切割与标签定量聚合酶链反应（CUT&Tag-qPCR）分析评估PRMT5抑制对毛细胞存活的机制。PRMT5的药理学抑制显著减轻了顺铂诱导的耳蜗毛细胞和螺旋神经节神经元损伤，并通过保护线粒体功能和防止活性氧积累减少了细胞凋亡。CUT&Tag-qPCR分析表明，抑制HEI-OC1细胞中的PRMT5可减少该基因启动子区域H4R3me2s/H3R8me2s标记的积累，从而激活该基因的表达。这些发现表明，PRMT5抑制剂作为抗顺铂诱导耳毒性的药物具有强大潜力，并可为听力损失治疗策略的进一步研究奠定基础。
