2. Academic Validation
  3. Supporting cells orchestrate noise-induced hearing loss via a Gasdermin D-dependent signaling loop with hair cells

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

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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