NADPH oxidase 3 inhibition preserves hearing in mice after stereotactic radiosurgery

Stereotactic radiosurgery (SRS) is a standard treatment for vestibular schwannoma but is associated with a substantial risk of progressive and irreversible hearing loss. NADPH oxidase 3 (NOX3), an enzyme predominantly expressed in the inner ear, has been identified as a key source of oxidative stress underlying cochlear injury. Using a mouse model of SRS-induced hearing loss, we found that genetic deletion of Nox3 preserved auditory function and protected cochlear structures, including hair cells, synaptic ribbons, and spiral ganglion neurons. Complementary experiments using local delivery of a small interfering RNA directed against Nox3 confirmed that transient inhibition markedly reduced hearing loss and tissue damage compared with scrambled controls. In addition, Nox3 inhibition attenuated radiation-induced lipid peroxidation and macrophage infiltration within the cochlea. These findings identify NOX3-derived oxidative stress as an important upstream mediator of SRS-induced ototoxicity and demonstrate that its inhibition confers significant functional and structural protection. Given the predictable timing of SRS in clinical settings, a NOX3-targeted intervention may offer a feasible and selective strategy to prevent hearing loss as an adjunct to tumor-directed treatment.