GATA4‐Driven Transcription of HtrA1 Promotes Cellular Senescence in Ménière's Disease and Age‐Related Audio‐Vestibular Dysfunction

ABSTRACT Ménière's disease (MD), a chronic inflammatory disorder with age‐related increased incidence, exhibits poorly understood pathogenesis and limited therapeutic options. Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence‐associated 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‐induced audio‐vestibular dysfunction and cellular senescence in mice and HEI‐OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA‐seq and ChIP‐seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV‐mediated HtrA1 overexpression exacerbates MD‐like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age‐related audio‐vestibular 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‐related audio‐vestibular disorders.