胆管癌（CCA）表现出糖酵解增强，这对于满足其恶性进展所固有的更高的能量需求至关重要。最近的研究表明，内源性糖原而不是外源性葡萄糖作为糖酵解的主要碳源，强调需要更好地了解 CCA 中糖原稳态的调节。在此，通过全面综合分析，我们发现参与糖原稳态的主要酶脑型糖原磷酸化酶（PYGB）在CCA组织中显着上调，可作为人类CCA患者的独立预后指标。此外，在类器官和异种移植模型中，PYGB 表达升高会增强胆管癌的发生并增强 CCA 细胞的增殖。缺氧以磷酸甘油酸激酶 1 (PGK1) 依赖性方式刺激 PYGB 活性，导致糖原分解并随后释放葡萄糖-6-磷酸 (G6P)，从而促进有氧糖酵解。值得注意的是，虚拟筛选确定 β 受体阻滞剂卡维地洛是 PYGB 的有效药理学抑制剂，可以减缓 CCA 进展。总的来说，这些发现使 PYGB 成为 CCA 有前景的预后生物标志物和治疗靶点。

Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative analysis, we identified that glycogen phosphorylase brain form (PYGB), the main enzyme involved in glycogen homeostasis, was markedly upregulated in CCA tissues, serving as an independent prognostic indicator for human CCA patients. Moreover, elevated PYGB expression potentiated cholangiocarcinogenesis and augmented CCA cell proliferation in both organoid and xenograft models. Hypoxia stimulated PYGB activity in a phosphoglycerate kinase 1 (PGK1)-dependent manner, leading to glycogenolysis and the subsequent release of glucose-6-phosphate (G6P) and thereby facilitating aerobic glycolysis. Notably, a virtual screening pinpointed the beta-blocker carvedilol as a potent pharmacological inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA.