PYGL (glycogen phosphorylase L) is an allosteric enzyme that catalyzes the phosphorolytic cleavage of glycogen to glucose-1-phosphate, serving as the rate-limiting step in glycogen catabolism and playing a central role in glucose homeostasis 1. As the hepatic glycogen phosphorylase enzyme, PYGL deficiency causes glycogen storage disease type VI, characterized by hepatomegaly, ketotic hypoglycemia, and impaired growth 1. Beyond its canonical metabolic role, PYGL functions as an oncogenic driver across multiple cancer types. In pancreatic cancer, hypoxia-induced PYGL promotes epithelial-mesenchymal transition and metastasis by mobilizing glycogen to fuel glycolysis 2. In liver cancer, PYGL deficiency leads to glycogen accumulation that undergoes phase separation, sequestering Hippo kinases to promote tumorigenesis 3. In head and neck squamous cell carcinoma, PYGL serves as a critical metabolic biomarker associated with poor prognosis, enhanced metastasis, and chemotherapy resistance through GSH/ROS/p53 pathway dysregulation 45. PYGL also regulates lactate metabolism and suppresses M1 macrophage polarization, reducing anti-tumor immunity 5. Importantly, neurons utilize PYGL-mediated glycogen catabolism for glycolytic plasticity under mitochondrial dysfunction and hypoxia, supporting synaptic function 6. Clinically, PYGL represents both a prognostic biomarker in glioma 7 and acute myocardial infarction 8, and an emerging therapeutic target for metabolically driven cancers.