胃癌（GC）仍然是一种死亡率高的全球性疾病，缺乏有效的治疗方法和毒副作用大是其预后不良的主要原因。因此，需要紧急努力寻找安全有效的治疗策略。绞股蓝苷 (Gyp) 是一种广泛使用的天然产物，可调节血糖以改善疾病进展，且毒副作用很少。鉴于异常糖代谢在驱动肿瘤恶性中的关键作用，探索 Gyp 与 GC 中糖代谢之间的关联并了解 Gyp 影响糖代谢的作用机制具有重要意义。在这项研究中，我们证明 Gyp 在体外和体内均可抑制 GC 增殖和迁移。我们利用网络药理学和代谢组学发现 Gyp 通过抑制糖酵解来抑制 GC 的恶性进展。转录组分析表明，Hippo 途径是 GC 中 Gyp 糖酵解的关键调节因子。此外，Gyp 诱导 LATS1/2 蛋白上调，导致 YAP 磷酸化增加和 TAZ 蛋白表达减少。 YAP 激动剂 XMU-MP-1 通过逆转糖酵解来挽救 Gyp 对 GC 增殖的抑制作用。这些发现证实，Gyp 通过 Hippo 途径靶向糖酵解来抑制 GC 增殖。我们的研究探讨了 Gyp 在 GC 恶性进展中的作用，探讨了其治疗前景，阐明了 Gyp 通过干扰糖酵解过程抑制 GC 增殖的机制，从而为 GC 患者提供了一种潜在的新型治疗策略。© 2024。作者。

Gastric cancer (GC) remains a global disease with a high mortality rate, the lack of effective treatments and the high toxicity of side effects are primary causes for its poor prognosis. Hence, urgent efforts are needed to find safe and effective therapeutic strategies. Gypenoside (Gyp) is a widely used natural product that regulates blood glucose to improve disease progression with few toxic side effects. Given the crucial role of abnormal glycometabolism in driving tumor malignancy, it is important to explore the association between Gyp and glycometabolism in GC and understand the mechanism of action by which Gyp influences glycometabolism. In this study, we demonstrated that Gyp suppresses GC proliferation and migration both in vitro and in vivo. We identified that Gyp suppresses the malignant progression of GC by inhibiting glycolysis using network pharmacology and metabolomics. Transcriptome analysis revealed that the Hippo pathway is a key regulator of glycolysis by Gyp in GC. Furthermore, Gyp induced upregulation of LATS1/2 proteins, leading to increased YAP phosphorylation and decreased TAZ protein expression. The YAP agonist XMU-MP-1 rescued the inhibitory effect of Gyp on GC proliferation by reversing glycolysis. These findings confirmed that Gyp inhibits GC proliferation by targeting glycolysis through the Hippo pathway. Our study examined the role of Gyp in the malignant progression of GC, explored its therapeutic prospects, elucidated a mechanism by which Gyp suppresses GC proliferation through interference with the glycolytic process, thus providing a potential novel therapeutic strategy for GC patients.© 2024. The Author(s).