Supporting cells orchestrate noise-induced hearing loss via a Gasdermin D-dependent signaling loop with hair cells

Noise-induced hearing loss (NIHL), a common sensory disorder, is traditionally thought to stem primarily from direct damage to sound-sensing hair cells (HCs). Here, we demonstrate that supporting cells (SCs), neighboring cells not previously implicated in NIHL pathogenesis, orchestrate hearing loss and HC degeneration through Gasdermin D (GSDMD) activation. Mechanistically, noise-induced oxidative stress in HCs triggers activation of epidermal growth factor receptor in SCs, leading to extracellular-regulated kinase phosphorylation and caspase-11-dependent cleavage of GSDMD, thereby establishing an HC-to-SC signaling cascade. Furthermore, GSDMD activation in SCs reciprocally exacerbates oxidative injury in HCs, creating a pathogenic positive feedback loop between the two cell types. Our findings uncover a central role for SCs in noise-induced hearing loss and identify GSDMD-mediated intercellular communication as a potential therapeutic target.

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Publication Details

Journal
Nature Communications
Published
2025-12-17
DOI
https://doi.org/10.1038/s41467-025-66152-6
Citations
2
Primary Topic
Hearing, Cochlea, Tinnitus, Genetics
Type
article
Field-Weighted Citation Impact
2.93
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Supporting cells orchestrate noise-induced hearing loss via a Gasdermin D-dependent signaling loop with hair cells

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Supporting cells orchestrate noise-induced hearing loss via a Gasdermin D-dependent signaling loop with hair cells

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article en
2 citations

Abstract

Noise-induced hearing loss (NIHL), a common sensory disorder, is traditionally thought to stem primarily from direct damage to sound-sensing hair cells (HCs). Here, we demonstrate that supporting cells (SCs), neighboring cells not previously implicated in NIHL pathogenesis, orchestrate hearing loss and HC degeneration through Gasdermin D (GSDMD) activation. Mechanistically, noise-induced oxidative stress in HCs triggers activation of epidermal growth factor receptor in SCs, leading to extracellular-regulated kinase phosphorylation and caspase-11-dependent cleavage of GSDMD, thereby establishing an HC-to-SC signaling cascade. Furthermore, GSDMD activation in SCs reciprocally exacerbates oxidative injury in HCs, creating a pathogenic positive feedback loop between the two cell types. Our findings uncover a central role for SCs in noise-induced hearing loss and identify GSDMD-mediated intercellular communication as a potential therapeutic target.

Nature CommunicationsVol. 16(1)
Shanghai University (CN), Dalhousie University (CA), Nanjing University of Chinese Medicine (CN), Shanghai Jiao Tong University (CN), Ruijin Hospital (CN), Shanghai University of Traditional Chinese Medicine (CN), Shanghai Zhangjiang Laboratory (CN), Shanghai Sixth People's Hospital (CN), Institute of Natural Science (KP)
Openalex Percentile: Top 8%
Hearing, Cochlea, Tinnitus, Genetics
2.93
DOIOpen Access PDFOpenAlex
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