耳蜗及感音神经性听力障碍中的泛素-蛋白酶体系统与蛋白质稳态
The ubiquitin-proteasome system and proteostasis in the cochlea and sensorineural hearing disorders.
文献信息
| PMID | 42864579 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Yiming Zhong |
| 作者单位 | Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2Nd Road, Shanghai, 200025, China. |
| 期刊 | Molecular biomedicine |
| SCI 分区 | Q1 |
| IF | 11.8 |
| 研究类型 | 综述 Meta · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
泛素-蛋白酶体系统（UPS）是细胞内蛋白质降解的主要机制，在维持所有组织的蛋白质稳态中发挥着不可或缺的作用。感音神经性听力损失影响着全球数十亿人，其特征是耳蜗毛细胞和螺旋神经节神经元的不可逆退化。然而，有效的治疗方法仍然缺乏。尽管UPS功能障碍在衰老和神经退行性疾病中日益被认识到，但其对耳蜗发育、稳态和听力障碍的具体贡献受到的关注相对有限。本综述系统总结了UPS介导的蛋白质稳态在听觉系统中的作用。本综述讨论了主要的UPS相关组分，包括E1/E2/E3泛素连接酶、去泛素化酶和蛋白酶体亚基。全面总结了UPS在耳蜗发育和内耳听觉功能维持中的重要性。总结了各种UPS分子及其在不同类型听力损失中的潜在致病机制或相关信号通路，包括先天性听力损失、年龄相关性听力损失、噪声性听力损失和药物相关性听力损失。本综述首次强调了UPS在耳蜗结构间的组织特异性功能差异。它还提出UPS作为连接听力损失中多种病理通路的中心调控枢纽，包括线粒体自噬、自噬、氧化应激、DNA损伤修复、内质网（ER）相关降解和NF-κB介导的炎症。最后，讨论了靶向UPS组分以恢复耳蜗蛋白质稳态和听力损失的新兴治疗策略。这些见解为开发针对感音神经性听力损失的UPS靶向干预措施奠定了坚实基础，以便未来根据耳蜗细胞特异性泛素组学实现精准治疗。
英文摘要
The ubiquitin-proteasome system (UPS) is the major machinery for intracellular protein degradation, playing an indispensable role in maintaining proteostasis across all tissues. Sensorineural hearing loss affects billions of people worldwide and is characterized by the irreversible degeneration of cochlear hair cells and spiral ganglion neurons. However, effective treatments remain unavailable. Although UPS dysfunction has been increasingly recognized in aging and neurodegenerative diseases, its specific contributions to cochlear development, homeostasis, and hearing disorders have received relatively limited attention. This review systematically summarizes the roles of UPS-mediated proteostasis in the auditory system. Major UPS related components including E1/E2/E3 ubiquitin ligases, deubiquitinating enzymes and proteasome subunits were discussed in this review. A comprehensive summary of the importance of UPS in cochlear development and the maintenance of inner ear auditory function has been made. Various UPS molecules and their potential pathogenic mechanisms or related signaling pathways are summarized in different types of hearing loss, including congenital hearing loss, age-related hearing loss, noise-induced hearing loss, and drug-related hearing loss. This review first highlights the tissue-specific functional divergence of UPS among cochlear structures. It also proposes the UPS as a central regulatory hub linking multiple pathological pathways in hearing loss including mitophagy, autophagy, oxidative stress, DNA damage repair, endoplasmic reticulum (ER) associated degradation, and NF-κB mediated inflammation. Finally, the emerging therapeutic strategies that target UPS components to restore cochlear proteostasis and hearing loss are discussed. These insights lay a solid foundation for developing UPS-targeted interventions for sensorineural hearing loss, in order to achieve precise treatments according to cochlear cell-specific ubiquitinomics in the future.