Circadian‐Related Serotonin/Melatonin Level Modulates Cisplatin Ototoxicity Susceptibility Depended on NOS3–NO Pathway

Jun 9, 2026Journal of pineal research

Daily Serotonin and Melatonin Levels May Influence Sensitivity to Cisplatin Hearing Damage Through a Nitric Oxide Pathway

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Abstract

Disrupted light exposure may significantly increase susceptibility to sensorineural hearing loss in mice.

Circadian rhythm disruption led to reduced melatonin and elevated serotonin levels in the inner ear.
In vivo and in vitro models showed that melatonin treatment protected hearing and reduced inner ear cell death.
Co-administration of serotonin worsened the damage from cisplatin treatment.
NOS3 was identified as a potential target for both melatonin and serotonin in regulating the NO signaling pathway.
Exogenous NOS3 supplementation mitigated cisplatin-induced hair cell damage under disrupted circadian conditions.

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Hearing impairment is attributed to factors such as age, genetic predisposition, and environmental influences, among which environmental factors are considered modifiable. Among various environmental factors, the role of poor lifestyle habits is particularly critical, yet the specific mechanisms by which they contribute to hearing damage remain unclear. This study reveals that dysregulated hormone levels due to disrupted light exposure may significantly increase susceptibility to sensorineural hearing loss. In mice, circadian rhythm disruption was found to reduce melatonin and elevate serotonin levels in the inner ear, thereby increasing vulnerability to cisplatin-induced ototoxicity. In both in vivo and in vitro cisplatin-treatment models, we showed that combined treatment with melatonin protected hearing, reduced inner ear cell death, and preserved synaptic connections, whereas serotonin co-administration exacerbated the damage. Using small molecule-protein interaction prediction, we identified NOS3 as a potential target of both melatonin and serotonin, through which they appear to regulate the NO signaling pathway and influence hair cell ferroptosis. Finally, exogenous supplementation of NOS3 in cochlear tissues effectively mitigated cisplatin-induced hair cell damage, even under conditions of circadian rhythm disruption. These findings indicate that the melatonin/serotonin balance modulates susceptibility to sensorineural hearing loss via the NOS3-NO signaling pathway.

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Circadian‐Related Serotonin/Melatonin Level Modulates Cisplatin Ototoxicity Susceptibility Depended on NOS3–NO Pathway

Abstract

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