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Although the combinatorial modulation of Notch and Wnt signaling robustly reprograms cochlear supporting cells to HCs in vitro, these strategies show limited success in vivo, which suggests that the native cochlear microenvironment imposes inhibitory cues. Here, we identify hypoxia-inducible factor 1\u03b1 (HIF1\u03b1) as a critical barrier to HC reprogramming in vivo. We found that HIF1\u03b1 accumulates in the basilar membrane of the intact cochlea, whereas ex vivo culture rapidly eliminates this accumulation. Mimicking the in vivo hypoxic state recapitulated the reprogramming blockade, hindering supporting cells from completing the fate transition to HCs. Mechanistically, HIF1\u03b1 selectively suppressed Wnt signaling, as evidenced by the reduced expression of Wnt target genes and Wnt10a. Importantly, the pharmacological inhibition of HIF1\u03b1 rescued the impaired reprogramming under hypoxia. These findings demonstrate that HIF1\u03b1 accumulation in the hypoxic cochlear environment antagonizes Wnt-mediated HC differentiation, providing a mechanistic explanation for the failure of in vivo regeneration. Targeting HIF1\u03b1 to restore supporting cell reprogramming competence within the hypoxic cochlear niche represents a promising, clinically translatable strategy for functional HC regeneration and hearing restoration.<\/jats:p>","DOI":"10.3390\/cells15161440","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:09:36Z","timestamp":1786435776000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia-Stabilized HIF1\u03b1 Restricts Hair Cell Reprogramming by Suppressing Wnt Signaling in the Mammalian Cochlea"],"prefix":"10.3390","volume":"15","author":[{"given":"Qing","family":"Liu","sequence":"first","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"},{"name":"Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanning","family":"Guo","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"},{"name":"Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7861-6313","authenticated-orcid":false,"given":"Ao","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"},{"name":"Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-9301","authenticated-orcid":false,"given":"Guoqiang","family":"Wan","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), the Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing 210008, China"},{"name":"Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing 210008, China"},{"name":"Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1056\/NEJMra1616601","article-title":"Hearing Loss in Adults","volume":"377","author":"Cunningham","year":"2017","journal-title":"N. 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