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In this study, we discovered a novel function of p21, which participated in the regulation of metabolic pathways under hypoxia. We found that p21 was upregulated in glioblastoma (GBM) cells under hypoxic conditions, which enhanced the radioresistance of GBM cells. In principle, HIF\u20101\u03b1 is bound directly to the hypoxia response elements (HREs) of the p21 promoter to enhance its transcription activity, in turn, p21 also promoted the transcription of HIF\u20101\u03b1 at the mRNA level and maintained HIF\u20101\u03b1 function under oxygen deficiency. The positive correlation between p21 and HIF\u20101\u03b1 augmented Glut1\/LDHA\u2010mediated glycolysis and aggravated the radioresistance of GBM cells. 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