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

  • Nat Commun. 2025 Dec 17;16(1):11181. doi: 10.1038/s41467-025-66152-6.
Lili Xiao  #  1  2  3 ,  Jianju Liu  #  4 ,  Yi Chen  1  2  3 ,  Liang Xia  1  2  3 ,  Yumeng Jiang  1  2  3 ,  Xiaoyan Chen  5 ,  Tianjiao Zhou  1  2  3 ,  Yan Sun  6 ,  Wen Lu  1  2  3 ,  Hui Wang  7  8  9 ,  Jian Wang  10  11 ,  Yanmei Feng  12  13  14 ,  Zhen Zhang  15  16  17 ,  Shankai Yin  1  2  3
Affiliations
  • 1. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
  • 3. Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China.
  • 4. School of Rehabilitation Science of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 5. Department of Otolaryngology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China.
  • 6. Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China.
  • 7. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China. [email protected].
  • 9. Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 10. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 11. School of Communication Science and Disorders, Dalhousie University, Halifax, NS, Canada. [email protected].
  • 12. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 13. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China. [email protected].
  • 14. Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 15. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 16. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China. [email protected].
  • 17. Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41407982 DOI: 10.1038/s41467-025-66152-6
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.

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