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 patients with CCA. 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-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 β-blocker carvedilol as a potent pharmacologic inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA.  Significance: Cholangiocarcinoma cells exhibit high glycogen phosphorylase activity under hypoxic conditions that mediates metabolic reprograming to promote glycolysis and support tumor development.

中文翻译：

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缺氧刺激 PYGB 酶活性，促进糖原代谢和胆管癌进展。


胆管癌 （CCA） 表现出增强的糖酵解，这对于满足其恶性进展固有的高能量需求至关重要。最近的研究表明，内源性糖原而不是外源性葡萄糖是糖酵解的主要碳源，这突出表明需要更好地了解 CCA 中糖原稳态的调节。在这里，通过全面的综合分析，我们确定参与糖原稳态的主要酶糖原磷酸化酶脑形式 （PYGB） 在 CCA 组织中显着上调，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 表达升高增强了胆管癌生成并增加了 CCA 细胞增殖。缺氧以磷酸甘油酸激酶 1 依赖性方式刺激 PYGB 活性，导致糖原分解和随后的葡萄糖-6-磷酸 （G6P） 释放，从而促进有氧糖酵解。值得注意的是，一项虚拟筛选确定 β 阻滞剂卡维地洛是一种有效的 PYGB 药物抑制剂，可以减轻 CCA 进展。总的来说，这些发现将 PYGB 定位为 CCA 有前途的预后生物标志物和治疗靶点。意义： 胆管癌细胞在缺氧条件下表现出高糖原磷酸化酶活性，介导代谢重编程以促进糖酵解并支持肿瘤发展。