Yu Mengjie, Yang Dou, Zhu Danxia, Wang Yue, Cao Minmin, Zhu Jingfeng, Zhu Wei, Wang Guangji, Aa Jiye
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, PR China.
J Pathol. 2025 Aug;266(4-5):465-480. doi: 10.1002/path.6442. Epub 2025 Jun 20.
Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (p < 0.001) and xanthine (p < 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by GMPS knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.
代谢重编程在肺腺癌（LUAD）的发生和发展中起着关键作用。然而，在对代谢重编程的主要驱动因素以及早期LUAD中的变化的理解方面仍存在很大差距。通过对来自三个独立临床中心的2531份血浆和血清样本进行无偏倚的大规模代谢组学分析，我们确定了嘌呤代谢的显著扰动，这是早期LUAD中重编程代谢的特征。此外，次黄嘌呤（p<0.001）和黄嘌呤（p<0.05）被确定为两个典型的早期风险指标，其优势比（OR）分别超过2.8和1.45。鸟苷单磷酸合成酶（GMPS）被确定为LUAD早期发展和恶性进展的关键因素。GMPS基因敲低显著减弱了LUAD的进展，而其过表达则明显加剧了LUAD的进展。进一步的数据表明，基于标记同位素代谢物的相对丰度，GMPS主要通过其酶活性和随后嘌呤核苷酸的产生，促成了LUAD的重编程代谢表型。总的来说，嘌呤代谢失调成为早期LUAD的一个关键特征，靶向GMPS活性可能为LUAD治疗提供有前景的治疗潜力。©2025年英国和爱尔兰病理学会。
