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Updated: Apr 16, 2026
Cochlear Surface Preparation in the Adult Mouse
Published on: November 6, 2019
GATA4-Driven Transcription of HtrA1 Promotes Cellular Senescence in Ménière's Disease and Age-Related
Na Zhang1,2, Na Li1,2,3, Yan Wang1,3
1Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China.
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.
Insights
Cellular senescence drives Ménière
Area of Science:
- Inner ear biology
- Cellular senescence
- Inflammaging
Background:
- Ménière's disease (MD) pathogenesis is poorly understood, with limited treatment options.
- Cellular senescence, characterized by mitochondrial dysfunction, reactive oxygen species (ROS), and senescence-associated secretory phenotype (SASP), is implicated.
- Increased incidence of MD is observed with aging.
Purpose of the Study:
- Investigate the role of cellular senescence in MD.
- Identify key molecular regulators and potential therapeutic targets for MD and age-related inner ear disorders.
Main Methods:
- Analysis of vestibular tissue from MD patients and a mouse model.
- Genetic deletion of transcription factor GATA4 in hair cells.
- RNA sequencing (RNA-seq) and ChIP sequencing (ChIP-seq).
- Pharmacological inhibition of HDAC6 and HtrA1 (Galegenimab).
Main Results:
- Cellular senescence markers are prevalent in MD vestibular tissue and a mouse model.
- GATA4 is upregulated in MD and its deletion ameliorates audio-vestibular dysfunction and senescence.
- HDAC6 restrains GATA4 nuclear transport; HtrA1 is a direct GATA4 target.
- HDAC6 inhibition or HtrA1 overexpression worsens MD phenotypes, while HtrA1 inhibition improves them.
- GATA4 deletion reduces age-related audio-vestibular deficits and senescence.
Conclusions:
- GATA4 is a critical regulator of cellular senescence and inflammaging in inner ear pathologies.
- Targeting GATA4, HDAC6, or HtrA1 offers potential therapeutic strategies for MD and age-related hearing and balance disorders.
