Hippo-YAP/TAZ signaling in inner ear development, injury, and regeneration: evidence synthesis and the biomechanical brake hypothesis.

Sensorineural hearing loss in mammals is essentially irreversible. Mature cochlear hair cells, once lost, do not regenerate. Non-mammalian vertebrates retain this ability, but in the mammalian organ of Corti, supporting cells lose their proliferative and transdifferentiation competence after birth. Reactivation of classical developmental pathways has also shown limited success in the adult cochlea. In this review, we first synthesize published evidence on Hippo-Yes-associated protein(YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in the inner ear, including studies of inner-ear progenitors, organ of Corti growth, vestibular sensory epithelia, cochlear hair-cell injury, neonatal cochlear regeneration models, and emerging adult cochlear data. On this basis, we then evaluate the biomechanical brake hypothesis, which proposes that injury-associated mechanical remodeling may interact with Hippo-YAP/TAZ signaling to restrict supporting-cell plasticity in the mature mammalian cochlea. Rather than presenting this hypothesis as an established mechanism, we treat it as an evidence-graded framework that must be tested against alternative explanations, including protective epithelial repair, cell-cycle inhibition, epigenetic restriction, and loss of developmental competence. The available literature suggests that Hippo-YAP/TAZ signaling participates in several inner-ear processes, including progenitor expansion, sensory epithelial growth, species-dependent vestibular repair, otoprotective responses, and supporting-cell proliferation under defined experimental conditions. However, direct evidence that injury-induced mechanical remodeling causally suppresses YAP/TAZ-dependent regeneration in the adult cochlea remains limited. We therefore distinguish among developmental, neonatal, vestibular,