Exosome-induced ferroptosis mediates cochlear hair cell injury via GPX4 suppression and iron overload

Abstract

Abstract Vestibular schwannoma (VS) is the most common benign tumor in the cerebellopontine angle, with approximately 95% of patients suffering sensorineural hearing loss (SNHL). Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated in cochlear hair cell vulnerability. However, its role in VS-associated SNHL remains poorly understood. In this study, we investigated whether VS-derived exosomes (VS-Exos) contribute to SNHL by inducing ferroptosis in cochlear hair cells. Proteomic and bioinformatic analyses were performed to compare exosomes from VS patients with poor hearing (PH-Exos) versus those with good hearing (GH-Exos). In vitro and in vivo experiments were conducted to assess the damaging effects of VS-Exos on cochlear hair cells and to evaluate the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Our results demonstrate that VS-Exos promote ferroptosis in cochlear hair cells by downregulating glutathione peroxidase 4 (GPX4) and disrupting iron homeostasis, leading to accumulation of ferrous ions, reactive oxygen species, and lipid peroxidation. Notably, PH-Exos induced significantly greater ferroptotic damage than GH-Exos. Treatment with Fer-1 effectively alleviated hair cell injury and preserved auditory function in vivo. These findings uncover a novel mechanism by which VS-Exos contribute to hearing loss through GPX4 suppression and iron dyshomeostasis, and suggest that targeting ferroptosis or exosome-mediated signaling may represent a promising therapeutic strategy for hearing preservation in VS.

The authors' abstract, as published at the source. Cell Death Discovery, 2026 · DOI ↗