Nox3, a multi-subunit NADPH oxidase, is functionally and structurally related to Nox1 and Nox2. It belongs to the NOX family of NADPH oxidases, which are responsible for transporting electrons across the plasma membrane to generate superoxide and other reactive oxygen species (ROS) [3,4]. Nox3's physiological functions may include contributing to post-translational processing of proteins, cellular signaling, and regulation of gene expression [3,4]. Genetic models, such as knockout (KO) mice, have been crucial in studying its functions.

In Nox3 mutant mice, vestibular function is perturbed due to a lack of otoconia, while only minor hearing alterations are noted [1]. Nox3-Cre knock-in mice were generated to study Nox3-expressing regions and cell types in the inner ear. Nox3 was found to be expressed in various cochlear cells, including supporting cells, outer and inner hair cells, and spiral ganglion neurons. Its expression increased with cisplatin, age, and noise insults, and Nox3-derived superoxide in cochleae was shown to induce sensorineural hearing loss (SNHL), with the extent of involvement being cisplatin-induced > age-related > noise-induced hearing loss [2]. Knockdown of Nox3 by siRNA pretreatment prevented cisplatin ototoxicity, as demonstrated by preserved hearing thresholds and inner ear sensory cells [5]. Intracochlear delivery of Nox3-siRNAs induced a robust temporal Nox3 downregulation, which could prevent cisplatin-chemotherapy-mediated ototoxicity and other forms of acquired hearing loss [6].

In conclusion, Nox3 is essential for otoconia formation and its misregulation can lead to inner ear pathologies, especially sensorineural hearing loss. Studies using Nox3 KO and Cre-knock-in mouse models have significantly advanced our understanding of its role in these processes, providing potential therapeutic targets for preventing and treating inner ear-related diseases such as cisplatin-induced, age-related, and noise-induced hearing loss [1,2,5,6].