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Clinical studies indicated that patients with DUOXA2 mutations present mucosal immune dysregulation and hypothyroidism. In addition, genetics screening in mouse models linked Duoxa2 deficiency to severe deafness, yet its pathogenic mechanism remains elusive. In this study, we demonstrated that Duoxa2 is essential for normal auditory function and clarified its underlying mechanism by establishing the Duoxa2 conditional knockout (cKO) mouse model. We found that Duoxa2 deficiency impairs the structure and function of outer hair cells (OHCs) and stria vascularis (SV), core auditory components, via disrupted thyroid hormone synthesis. Duoxa2 cKO mice exhibited disorganized stereociliary bundles in OHCs, altered distribution patterns of the critical KCNQ4, aberrant ribbon synapse localization, and capillary dilation within the intermediate cell layer of SV. Notably, Atoh1-Cre drivers not only express Cre recombinase in hair cells but also show high expression in thyroid. This finding elucidates the reduced thyroid hormone levels in Atoh1-Duoxa2\u2212\/\u2212 mice and reveals an indirect mechanism affecting cochlear function. While postnatal thyroid hormone supplementation completely reversed these pathological changes, the effect was minimal in adulthood. Our findings provided insights into the intrinsic link between distinct thyroid disorders and hearing impairment and offered evidence for clinical intervention in patients with DUOXA2 variants.<\/jats:p>","DOI":"10.1093\/hmg\/ddag104","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:32:01Z","timestamp":1790508721000},"source":"Crossref","is-referenced-by-count":0,"title":["DUOXA2-mediated thyroid hormone synthesis is indispensable for postnatal maturation of auditory function"],"prefix":"10.1093","volume":"35","author":[{"given":"Wen","family":"Li","sequence":"first","affiliation":[{"name":"School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences , No. 6699 Qingdao Road, Huaiyin District, Jinan, Shandong 250117 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