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

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.