代谢异常已成为癌症的显着标志，并在肺腺癌（LUAD）的癌变和进展中发挥着关键作用。在这项研究中，单细胞测序表明，代谢酶6-磷酸葡萄糖酸脱氢酶（PGD）是磷酸戊糖途径（PPP）的关键调节因子，在恶性进展过程中恶性上皮细胞亚群中的表达显着上调。然而，PGD 在 LUAD 中的确切功能意义及其潜在机制仍然难以捉摸。通过TCGA数据库分析和LUAD组织芯片数据整合，发现LUAD中PGD表达显着上调，且与LUAD患者不良预后密切相关。此外，体外和体内分析表明，PGD 敲除和抑制其活性可减轻 LUAD 细胞的增殖、迁移和侵袭。从机制上讲，免疫沉淀-质谱 (IP-MS) 首次揭示 IQGAP1 是一种强大的新型 PGD 相互作用蛋白。 PGD​​ 通过与已知 AMPKα 结合伴侣 IQGAP1 的 IQ 结构域竞争性相互作用来降低 p-AMPK 水平，IQGAP1 促进 LUAD 细胞中的糖酵解和脂肪酸合成。此外，我们证明大黄素甲醚（一种 PGD 特异性抑制剂）和二甲双胍（一种 AMPK 激动剂）的组合可以在体内和体外更有效地抑制肿瘤生长。总的来说，这些发现表明 PGD 是 LUAD 的潜在预后生物标志物和治疗靶点。版权所有 © 2024。由 Elsevier B.V. 出版。

Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.Copyright © 2024. Published by Elsevier B.V.