TMPRSS3 is a transmembrane serine protease essential for hearing and cochlear hair cell survival. 1 The gene functions as a critical component of auditory system development and maintenance, with expression concentrated in the organ of Corti, lateral wall structures, and minimal expression in spiral ganglion neurons. 2 Biallelic TMPRSS3 mutations cause autosomal recessive nonsyndromic hearing loss (DFNB8/DFNB10), characterized by severe-to-profound sensorineural hearing loss with variable onset and progressive course depending on mutation type and location. 1 The c.916G>A (p.Ala306Thr) missense mutation is the most frequently reported variant across populations. 1 In a cohort of 406 families with childhood-onset hearing loss, TMPRSS3 mutations were identified in affected individuals, with 85% of those receiving cochlear implants reporting favorable outcomes and among the highest speech perception scores across all genotypes. 3 TMPRSS3 represents a promising candidate for gene therapy development. 4 Recent preclinical studies demonstrate that single AAV2-mediated TMPRSS3 gene delivery restores auditory function in aged mice carrying human DFNB8 mutations, rescuing both hair cells and spiral ganglion neurons. 5 6 These findings suggest TMPRSS3 gene therapy could serve as standalone treatment or combined with cochlear implantation for DFNB8/DFNB10 patients.