The Nrf2/GPX4 antioxidant pathway suppresses ferroptosis to protect against hearing impairment in cochlear ischemia-reperfusion injury

  • Int Immunopharmacol. 2025 Oct 15:167:115655. doi: 10.1016/j.intimp.2025.115655.
Ting Zou  1 ,  Sihan Huang  2 ,  Renwei Xie  3 ,  Jun Liu  4
Affiliations
  • 1. Department of Otorhinolaryngology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 2. Department of Otorhinolaryngology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3. Department of Otorhinolaryngology, Renhe Hospital, Baoshan District, Shanghai, China. Electronic address: [email protected].
  • 4. Department of Otorhinolaryngology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 41101226 DOI: 10.1016/j.intimp.2025.115655
Abstract

The prevalence of sudden sensorineural hearing loss (SSNHL) has been steadily increasing. Injury of Ischemia-reperfusion (I/R) is closely linked to SSNHL, but its exact mechanisms are not fully understood. This study demonstrates that Ferroptosis mediates I/R-induced cochlear damage and that the Nuclear factor erythroid 2-related factor 2 (Nrf2) agonist oltipraz (OPZ) confers protection. In vitro, marginal cells (MCs) subjected to oxygen-glucose deprivation/reperfusion (OGD/R) exhibited a pronounced rise in Reactive Oxygen Species (ROS), mitochondrial shrinkage, and a cell death rate of 25 %, consistent with the characteristic features of Ferroptosis. OPZ (10 μM) treatment doubled Glutathione Peroxidase 4 (GPX4) expression, suppressed ROS, and reduced the cell death rate to 14 %. These protective effects were abolished by Nrf2 knockdown. In vivo, rats subjected to I/R of the cochlea exhibited ∼39 dB threshold elevation, stria vascularis (SV) damage, and increased Ferroptosis. OPZ (75 mg/kg) administration preserved SV ultrastructure and restored hearing function (threshold improvement of ∼26 dB). These data highlight Ferroptosis as a key driver of I/R-induced SSNHL and establish Nrf2/HO-1 activation as a therapeutic strategy, with OPZ showing potential clinical relevance.

Keywords
Cochlea ischemia/reperfusion injury; Ferroptosis; Nuclear factor erythroid 2-related factor 2; Oxidative stress; SSNHL; Stria vascularis.
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