Luteolin Protects Against Noise‐Induced Hearing Loss via Mitigating Oxidative Stress and Apoptosis, With Potential Regulation of the <scp>EGR1</scp> / <scp>SPRY4</scp> Axis

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.