Hair cell (HC) loss, frequently induced by ototoxic agents such as gentamicin, leads to irreversible hearing loss. Because of the restricted regenerative capabilities of the mammalian inner ear, the exploration of therapeutic strategies to restore damaged HCs is critically needed. Recombinant human Neuritin (rhNeuritin), a neurotrophic factor with established roles in promoting cell survival and regeneration across various systems, presents itself as a promising therapeutic candidate for HC repair. In this study, we elucidate the protective effects of rhNeuritin on injured HCs and its capacity to facilitate HC regeneration post-damage. Through the use of cochlear Supporting Cell (SC) lineage-tracing models in neonatal mice, we demonstrate that SC trans-differentiation serves as the origin of HC regeneration following damage. Simultaneously, we uncover that rhNeuritin potentiates the proliferation of SC precursor cells. Mechanistic insights reveal that rhNeuritin-induced cochleae exhibit downregulation of the critical Notch pathway mediator, Hes1, and upregulation of the essential FGFR pathway component Erm, which together may underpin HC regeneration and the proliferation of SC precursors. Notably, rhNeuritin demonstrates significant preservation of HC structural integrity. These findings collectively highlight the therapeutic potential of rhNeuritin in addressing hearing loss resulting from HC damage, thereby opening a new avenue for the restoration of auditory function.

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http://dx.doi.org/10.1016/j.neuint.2025.105935DOI Listing

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