Therapeutic restoration of miR-96 prevents hearing loss in mice through modulation of noise-induced and genetic pathways

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-04 DOI:10.1016/j.isci.2025.112355

Ruilong Xia , Chenxi Jin , Siying Fei , Tingting Dong , Ting Wen , Fengting Zhu , Yunxin Shi , Qian Zhou , Yong Tao , Changgeng Peng

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Abstract

Hearing loss often arises from impairments in multiple genes, complicating therapeutic development. MicroRNAs, as master regulators, offer promising targets for complex diseases. We explored miR-96’s roles in hair cell (HC) function and noise-induced hearing loss (NIHL), finding that miR-96^−/−, not miR-96^+/−, mice exhibited progressive hearing loss due to gene regulatory network dysregulation from miR-96 loss in HCs not spiral ganglion neurons (SGNs). Viral-mediated delivery of miR-96 into the inner ear partially rescued hearing of miR-96^−/− mice. Tamoxifen-induced depletion of miR-96 in adult UBC^CreERT2/+; miR-96^fl/fl mice led to hearing loss, with Bach2, Gabra2, Gabra4, and Grk1 upregulation and Tnn, Col11a1, Gjb3, and Hnf4a downregulation. Furthermore, noise trauma reduced miR-96, altering Bach2, Bcl2l1, Slc26a9, Gabrb1, Grk1, Nos2, and Cyp1a1 expression, whereas miR-96 overexpression protected hearing against noise by reversing the expression of Bach2, Bcl2l1, and Cyp1a1. Our findings underscore miR-96’s essential role in adult hearing maintenance and NIHL prevention, presenting it as a promising therapeutic target.

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治疗性恢复miR-96通过调节噪声诱导和遗传途径防止小鼠听力损失

听力损失通常是由多个基因的损伤引起的，使治疗发展复杂化。MicroRNAs作为主调控因子，为复杂疾病提供了有希望的靶点。我们探索了miR-96在毛细胞（HC）功能和噪声性听力损失（NIHL）中的作用，发现miR-96−/−，而不是miR-96+/−，小鼠表现出进行性听力损失，是由于HCs中miR-96缺失而不是螺旋神经节神经元（sgn）中的基因调控网络失调。病毒介导的miR-96进入内耳部分恢复了miR-96−/−小鼠的听力。他莫昔芬诱导成人UBCCreERT2/+中miR-96的缺失miR-96fl/fl小鼠导致听力损失，Bach2、Gabra2、Gabra4和Grk1上调，Tnn、Col11a1、Gjb3和Hnf4a下调。此外，噪声创伤降低了miR-96，改变了Bach2、Bcl2l1、Slc26a9、Gabrb1、Grk1、Nos2和Cyp1a1的表达，而miR-96过表达通过逆转Bach2、Bcl2l1和Cyp1a1的表达来保护听力免受噪声的影响。我们的研究结果强调了miR-96在成人听力维持和NIHL预防中的重要作用，表明它是一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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