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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\u2010induced ototoxicity. In both in vivo and in vitro cisplatin\u2010treatment models, we showed that combined treatment with melatonin protected hearing, reduced inner ear cell death, and preserved synaptic connections, whereas serotonin co\u2010administration exacerbated the damage. Using small molecule\u2013protein 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\u2010induced 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\u2013NO signaling pathway.<\/jats:p>","DOI":"10.1111\/jpi.70154","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:21:11Z","timestamp":1781011271000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circadian\u2010Related Serotonin\/Melatonin Level Modulates Cisplatin Ototoxicity Susceptibility Depended on NOS3\u2013NO Pathway"],"prefix":"10.1111","volume":"78","author":[{"given":"Siyu","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, ENT Institute and NHC Key Laboratory of Hearing Medicine, Eye &amp; ENT Hospital Fudan University Shanghai China"},{"name":"Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, and MOE Frontiers Center for Brain Science Fudan University Shanghai 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