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Hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) is subject to cell\u2010type\u2010specific AGE\u2010mediated regulation. In the current study, we assessed the mechanistic relationship between AGE accumulation and HIF\u20101\u03b1 degradation in NPCs. Immunohistochemical staining of degenerated nucleus pulposus (NP) samples was used to assess AGE levels. AGE impact on NPC survival and glycolysis\u2010related gene expression was assessed via 3\u2010(4,5)\u2010dimethylthiazol(\u2010z\u2010y1)\u20103,5\u2010di\u2010phenyltetrazolium bromide assay and quantitative reverse\u2010transcription polymerase chain reaction (qRT\u2010PCR), while HIF\u20101\u03b1 expression in NPCs following AGE treatment was monitored via Western blot analysis and qRT\u2010PCR. Additionally, a luciferase reporter assay was used to monitor HIF\u20101\u03b1 transcriptional activity. The importance of the receptor for activated C\u2010kinase 1 (RACK1) as a mediator of HIF\u20101\u03b1 degradation was evaluated through gain\u2010 and loss\u2010of\u2010function experiments. Competitive binding of RACK1 and HSP90 to HIF\u20101\u03b1 was evaluated via immunoprecipitation. Increased AGE accumulation was evident in NP samples from diabetic patients, and AGE treatment resulted in reduced HIF\u20101\u03b1 protein levels in NPCs that coincided with reduced HIF\u20101\u03b1 transcriptional activity. AGE treatment impaired the stability of HIF\u20101\u03b1, leading to its RACK1\u2010mediated proteasomal degradation in a manner independent of the canonical PHD\u2010mediated degradation pathway. Additionally, RACK1 competed with HSP90 for HIF\u20101\u03b1 binding following AGE treatment. AGE treatment of NPCs leads to HIF\u20101\u03b1 protein degradation. RACK1 competes with HSP90 for HIF\u20101\u03b1 binding following AGE treatment, resulting in posttranslational HIF\u20101\u03b1 degradation. These results suggest that AGE is an intervertebral disc degeneration risk factor, and highlight potential avenues for the treatment or prevention of this disease.<\/jats:p>","DOI":"10.1002\/cbin.11574","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T11:07:11Z","timestamp":1614078431000},"page":"1316-1326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["RACK1 mediates the advanced glycation end product\u2010induced degradation of HIF\u20101\u03b1 in nucleus pulposus cells via competing with HSP90 for HIF\u20101\u03b1 binding"],"prefix":"10.1002","volume":"45","author":[{"given":"Yi\u2010Chang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The First Affiliated Hospital of Soochow University  Suzhou 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