Roles of Ferrostatin-1 and Resveratrol in Noise-Induced Hearing Loss: Distinct Protection via Ferroptosis and Oxidative-Apoptotic Pathways.

Abstract

BACKGROUND: Noise-induced hearing loss (NIHL) is a common sensorineural disorder involving oxidative stress, apoptosis and emerging ferroptosis. Although ferroptosis inhibition and antioxidative therapies exert protective effects, their comparative mechanisms in NIHL remain unclear. This study compared the protective effects of ferrostatin-1 (Fer-1) and resveratrol (RSV) in an acute NIHL model. METHODS: Acute acoustic trauma was induced in mice by 2&#x2009;h broadband noise exposure (99-100&#x2009;dB SPL, 2-20&#x2009;kHz). Animals were assigned to Control, Noise, Noise&#x2009;+&#x2009;Fer-1 and Noise&#x2009;+&#x2009;RSV groups. Auditory brainstem response (ABR) thresholds were assessed to evaluate hearing function. Cochlear injury, apoptosis, oxidative stress and ferroptosis-related changes were examined via lactate dehydrogenase release, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, biochemical assays and Western blot analysis. RESULTS: Noise exposure significantly elevated ABR thresholds and induced cochlear hair-cell injury, oxidative stress and apoptosis ( P < 0.01). Fer-1 and RSV significantly attenuated hearing threshold shifts and structural injury compared with the Noise group ( P < 0.01). Fer-1 preferentially suppressed lipid peroxidation and restored glutathione peroxidase 4 expression, whereas RSV predominantly exerted antioxidative effects, including increased superoxide dismutase activity and reduced reactive oxygen species and malondialdehyde levels and attenuated apoptotic signalling reflected by decreased B-cell lymphoma 2 (Bcl-2)-associated X protein, increased Bcl-2 and reduced cleaved caspase-3 and p53 expressions ( P < 0.05). CONCLUSION: Fer-1 and RSV confer protection against NIHL through distinct pathway-biased mechanisms. Fer-1 primarily targets ferroptosis, whereas RSV predominantly alleviates oxidative stress and apoptosis, providing mechanistic insights into multipathway therapeutic strategies in NIHL.