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However, it exhibits significant heterogeneity in terms of both clinical presentation and biological basis. This review focuses on mechanism-oriented therapeutic strategies for GJB2-associated hearing loss, investigating how different types of GJB2 variants correspond to distinct clinical phenotypes and underlying pathogenic mechanisms, and aims to determine appropriate treatments. Current evidence suggests that GJB2-associated hearing loss is not solely caused by channel dysfunction resulting from gap junction defects, but rather the result of multiple pathological processes, including impaired GJB2 transcriptional regulation, cochlear developmental abnormalities, sensory epithelial degeneration and secondary damage pathways such as inflammation. Consequently, emerging therapeutic approaches can be viewed as interventions targeting specific mechanisms, including gene therapy, restoration of protein transport and pharmacological modulation of damage to the cochlear microenvironment. Overall, this review highlights the importance of aligning therapeutic strategies with specific GJB2 variants, underlying pathogenic mechanisms, and the developmental window during which cochlear injury remains biologically reversible.<\/jats:p>","DOI":"10.3390\/ijms27104313","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Recent Progress in Mechanism-Based Therapies for GJB2-Related Hearing Loss"],"prefix":"10.3390","volume":"27","author":[{"given":"Chengzhi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6922-4675","authenticated-orcid":false,"given":"Xiaohui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"},{"name":"Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1771-3715","authenticated-orcid":false,"given":"Yu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"},{"name":"Institute of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"},{"name":"Hubei Province Clinic Research Center for Deafness and Vertigo, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Podury, A., Jiam, N.T., Kim, M., Donnenfield, J.I., and Dhand, A. 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