代谢重编程被认为是化疗抗性的一种新兴机制，但胰腺导管腺癌（PDAC）的代谢特征尚不清楚。在这里，我们对PDAC器官oid的代谢组学特征进行了表征，并将其分为葡萄糖代谢型PDAC（高葡萄糖代谢水平）和脂质代谢型PDAC（高脂质代谢水平）。与脂质代谢型PDAC相比，葡萄糖代谢型PDAC对化疗更具抗性，并且患有葡萄糖代谢型PDAC的患者预后更差。综合分析揭示了GLUT1/aldolase B（ALDOB）/葡萄糖-6-磷酸脱氢酶（G6PD）轴通过重新塑造葡萄糖代谢来诱导葡萄糖代谢型PDAC的化疗抗性。在表达GLUT1高、ALDOB低的葡萄糖代谢型PDAC中，检测到糖酵解通量增加、G6PD活性增加和嘧啶生物合成，并且这些表型可以通过抑制GLUT1表达或增加ALDOB表达来逆转。药物抑制GLUT1或G6PD可以增强葡萄糖代谢型PDAC对化疗的响应。我们的发现揭示了PDAC中与化疗敏感性差异相关的潜在代谢异质性，并通过化疗和GLUT1/ALDOB/G6PD轴抑制剂的联合发展了一种有前景的药物策略，用于化疗抗性的葡萄糖代谢型PDAC患者。版权所有 © 2023 作者。由Elsevier Inc.出版。版权所有。

Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.