MITF-SCD1 lipid metabolic axis prevents ouabain-induced spiral ganglion neuron ferroptosis and hearing loss.

Damage to cochlear spiral ganglion neurons (SGNs) causes irreversible sensorineural hearing loss (SNHL), yet the underlying degenerative mechanisms remain elusive, impeding targeted therapies. Here, we established an auditory neuropathy model using the ototoxic drug ouabain to induce selective SGN injury. Transcriptomic profiling revealed a ferroptosis-linked gene signature, with functional assays confirming ferroptotic damage in SGNs. Pharmacological inhibition of ferroptosis mitigated SGN loss and hearing impairment. Lipidomics demonstrated dysregulated fatty acid metabolism with an elevated saturated-to-monounsaturated fatty acid ratio, accompanied by downregulation of stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme for monounsaturated fatty acid synthesis. Restoring SCD1 activity through SCD1 overexpression or monounsaturated fatty acid supplementation mitigated ouabain-induced ferroptosis in SGNs and preserved auditory function, whereas genetic ablation of SCD1 aggravated degeneration. Bioinformatic screening and chromatin immunoprecipitation-PCR identified microphthalmia-associated transcription factor (MITF) as a direct upstream transcriptional regulator of SCD1. MITF overexpression restored SCD1 expression, suppressed ferroptosis, and improved SGN survival, whereas disruption of the MITF-SCD1 axis abrogated these protective effects, which were further validated in a cisplatin ototoxicity model. Collectively, these findings reveal an MITF-SCD1 lipid metabolic axis that safeguards SGNs against ferroptosis by sustaining SCD1-dependent lipid desaturation, highlighting a promising therapeutic target for SNHL.