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Background: Gliomas are highly aggressive brain tumors with complex metabolic and molecular alterations. The role of glycolysis in glioma progression and its regulation by hypoxia remain poorly understood. This study investigated the function of glycogen phosphorylase L ( PYGL ) in glioma and its interaction with glycolytic pathways under hypoxic conditions., Methods: Differential expression analysis was conducted using The Cancer Genome Atlas (TCGA) glioma and GSE67089 datasets, revealing significant changes in the expression of genes. A prognostic risk model incorporating PYGL was built by univariate and multivariate Cox regression analyses. The impacts of PYGL on glioma cell proliferation, glycolysis, apoptosis, and metabolic activities were evaluated by in vitro assays. Additionally, the influences of hypoxia and hypoxia-inducible factor 1-alpha ( HIF1α ) on PYGL expression were evaluated., Results: Our prognostic prediction model showed a C-index of 0.76 [95% confidence interval (CI): 0.70-0.82], indicating a good predictive accuracy of the model. In addition, genetic predictors included in the nomogram included PYGL, HIF1α, and other genes associated with the glycolytic pathway. Differential expression analysis identified PYGL as a key gene associated with glioma survival. PYGL expression was significantly upregulated in glioma cells. PYGL knockdown inhibited cell invasion, proliferation, migration, and colony formation and enhanced apoptosis via modulation of Bcl-2, caspase-3, and Bax. Glycolysis was impaired in PYGL -knockdown cells, as indicated by increased glycogen levels and a reduced extracellular acidification rate (ECAR), adenosine triphosphate (ATP) levels, lactate levels, and PKM2 and LDHA expression. PYGL overexpression promoted glycolysis and cell viability, which was counteracted by 2-deoxy-D-glucose (2-DG). Hypoxia-induced PYGL expression was regulated by HIF1α , underscoring the interplay between the hypoxia and glycolysis pathways., Conclusions: PYGL is a crucial regulator of glycolysis in gliomas and contributes to tumor progression under hypoxic conditions. Targeting PYGL and its associated metabolic pathways may offer new therapeutic strategies for glioma treatment., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1974/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)