Neuritin protects spiral ganglion neurons via NKA-Ca²⁺ homeostasis and CaMKII/MAPK suppression

Spiral ganglion neurons (SGNs) are indispensable for auditory transduction, yet no approved pharmacological therapy exists for sensorineural hearing loss (SNHL). Neuritin has shown neuroprotective effects in the cochlea, but its mechanisms remain unclear. Here, we used a cochlear SGN-specific Neuritin conditional knockout mouse model and an ouabain‑induced SGN injury model to define the role of Neuritin in auditory neuropathy. Neuritin deficiency accelerated age‑related SGNs loss, synaptic degeneration, and progressive elevation of ABR thresholds. Conversely, round‑window delivery of recombinant human Neuritin improved high‑frequency hearing, preserved SGNs density, and restored ribbon synapses after ouabain injury. Transcriptomic profiling of cochlear tissue suggested enrichment of calcium signaling and MAPK pathways. Consistent with these results, Neuritin increased Na⁺/K⁺‑ATPase (NKA) activity, reduced intracellular Ca²⁺ overload, and suppressed phosphorylation of CaMKII and MAPK subfamilies (ERK1/2, p38, JNK). In primary cochlear explants and neuronal cell models, calcium chelation phenocopied the effects of Neuritin, whereas a MAPK activator partially reversed Neuritin‑mediated protection, including reduced apoptosis and improved neurite integrity. These findings support a model in which Neuritin maintains NKA‑dependent calcium homeostasis and restrains CaMKII/MAPK signaling to protect SGNs and auditory function. The study identifies Neuritin‑centered signaling as a therapeutic entry point for SNHL associated with SGN injury.