FOXO1-NCOA4 Axis Contributes to Cisplatin-Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy

Mammalian cochlea spiral ganglion neurons (SGNs) are crucial for sound transmission, they can be damaged by chemotherapy drug cisplatin and lead to irreversible sensorineural hearing loss (SNHL), while such damage can also render cochlear implants ineffective. However, the mechanisms underlying cisplatin-induced SGNs damage and subsequent SNHL are still under debate and there is no currently effective clinical treatment. Here, this study demonstrates that ferroptosis is triggered in SGNs following exposure to cisplatin. Inhibiting ferroptosis protects against cisplatin-induced SGNs damage and hearing loss, while inducing ferroptosis intensifies these effects. Furthermore, cisplatin prompts nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in SGNs, while knocking down NCOA4 mitigates cisplatin-induced ferroptosis and hearing loss. Notably, the upstream regulator of NCOA4 is identified and transcription factor forkhead box O1 (FOXO1) is shown to directly suppress NCOA4 expression in SGNs. The knocking down of FOXO1 amplifies NCOA4-mediated ferritinophagy, increases ferroptosis and lipid peroxidation, while disrupting the interaction between FOXO1 and NCOA4 in NCOA4 knock out mice prevents the cisplatin-induced SGN ferroptosis and hearing loss. Collectively, this study highlights the critical role of the FOXO1-NCOA4 axis in regulating ferritinophagy and ferroptosis in cisplatin-induced SGNs damage, offering promising therapeutic targets for SNHL mitigation. This study demonstrates that NCOA4-mediated ferritinophagy and ferroptosis are induced in spiral ganglion neurons (SGNs) following chemotherapy drug cisplatin treatment. FOXO1 acts as a direct upstream regulator of NCOA4, inhibiting NCOA4-mediated ferritinophagy and alleviating cisplatin-induced SGN ferroptosis and hearing loss. These findings confirm the role of the FOXO1-NCOA4 axis in regulating ferritinophagy and ferroptosis in response to cisplatin-induced SGN damage, highlighting promising therapeutic targets for mitigating sensorineural hearing loss. image