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Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence\u2010associated secretory phenotype (SASP), is prevalent in the vestibular tissue of MD patients and an endolymphatic hydrops mouse model. The transcription factor GATA4 is upregulated in MD and mice, and its genetic deletion in hair cells alleviates LPS\u2010induced audio\u2010vestibular dysfunction and cellular senescence in mice and HEI\u2010OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA\u2010seq and ChIP\u2010seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV\u2010mediated HtrA1 overexpression exacerbates MD\u2010like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age\u2010related audio\u2010vestibular deficits and senescence markers. Collectively, our findings establish GATA4 as a critical regulator of cellular senescence and inflammaging in inner ear pathologies, providing promising therapeutic targets for MD and age\u2010related audio\u2010vestibular disorders.<\/jats:p>","DOI":"10.1002\/advs.202512538","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:45:38Z","timestamp":1776195938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GATA4\u2010Driven Transcription of HtrA1 Promotes Cellular Senescence in M\u00e9ni\u00e8re's Disease and Age\u2010Related Audio\u2010Vestibular Dysfunction"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3955-3465","authenticated-orcid":false,"given":"Na","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Shandong Provincial ENT Hospital Shandong University  Jinan Shandong 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