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Although inflammation is increasingly recognized as a key contributor to cochlear degeneration, the therapeutic potential of targeting early inflammatory signaling remains poorly understood. Here, we combined phenotypic screening in zebrafish with mechanistic and functional validation in complementary mouse models to identify quinoxaline derivatives with otoprotective activity following acoustic trauma. Lead compounds preserved cochlear synapses and auditory function after moderate noise exposure, while one derivative also protected sensory hair cells in a model of permanent hearing loss. Mechanistic analyses demonstrated that this protection was associated with attenuation of early NF-\u03baB signaling and modulation of the cochlear inflammatory response toward a reparative state, consistent with suppression of pathogenic innate immune activation before irreversible tissue damage occurred. Together, these findings identify early NF-\u03baB-dependent inflammatory signaling as a therapeutically actionable mechanism in NIHL and establish quinoxaline derivatives as promising candidates for pharmacological intervention. More broadly, this work demonstrates the utility of a cross-species discovery platform for identifying therapies that preserve sensory function by targeting early inflammatory pathways.<\/jats:p>","DOI":"10.64898\/2026.07.11.737965","type":"posted-content","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T21:40:18Z","timestamp":1784324418000},"source":"Crossref","is-referenced-by-count":0,"title":["Resolving early cochlear inflammation prevents lasting damage from noise exposure"],"prefix":"10.64898","author":[{"given":"Lauren","family":"Barbush","sequence":"first","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klim","family":"Fedorchuk","sequence":"additional","affiliation":[{"name":"Rochester Institute of Technology \u2013 Rochester, NY 14623"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Ezzat","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0621-198X","authenticated-orcid":false,"given":"Vijayprakash Namakkal","family":"Manickam","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-4304","authenticated-orcid":false,"given":"Dinesh","family":"Gawande","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayden","family":"Chavez","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6520-988X","authenticated-orcid":false,"given":"Marisa","family":"Zallocchi","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine \u2013 Biomedical Sciences Department-Omaha, NE 68178"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072105501476000_2026.07.11.737965v1.1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.13.128728"},{"key":"2026072105501476000_2026.07.11.737965v1.2","unstructured":"Hearing Loss Prevention: Improvements to DOD Hearing Conservation Programs Could Lead to Better Outcomes | U.S. GAO. https:\/\/www.gao.gov\/products\/gao-11-114."},{"key":"2026072105501476000_2026.07.11.737965v1.3","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1097\/MOO.0000000000000083","article-title":"Noise-induced hearing loss: a military perspective","volume":"22","year":"2014","journal-title":"Curr. 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