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.
