Abstract

Aims Noise-induced hearing loss (NIHL) is a globally prevalent disorder caused by oxidative stress-mediated hair cell death, with no effective clinical treatments. This study explored the protective effect of luteolin (LL), a natural antioxidant flavonoid, against NIHL and its underlying molecular mechanism. Methods In vivo, mice received intratympanic LL injections around noise exposure, followed by ABR testing and cochlear immunofluorescence staining. In vitro, cochlear explants and HEI-OC1 cells were pretreated with LL, followed by the induction of oxidative stress using tert-butyl hydroperoxide (TBHP). Cellular viability, oxidative stress, and apoptosis were assessed. CRISPR/Cas9 technique was used to establish an Early growth response 1 (EGR1) knockout cell line. ChIP-PCR and dual-luciferase reporter assays clarified molecular mechanisms. Results Intratympanic LL significantly attenuated noise-induced auditory threshold elevation and outer hair cell loss in mice without affecting normal hearing. In vitro, LL dose-dependently mitigated TBHP-induced damage via regulating oxidative stress and apoptotic pathways, reversed TBHP-induced EGR1 upregulation, EGR1 knockout enhanced oxidative stress resistance, and EGR1 directly regulated sprouty RTK signaling antagonist 4 (SPRY4) transcription, while LL inhibited TBHP-induced SPRY4 upregulation. Conclusion Luteolin protects against NIHL by alleviating oxidative stress and suppressing apoptosis, with potential involvement of the EGR1/SPRY4 signaling axis, representing a promising candidate for NIHL prevention.