Page 139 - 南京医科大学自然版

第46卷第10期 陈奕文，张静静，张雄飞. 谷氨酰胺代谢和肿瘤耐药机制研究进展［J］.
2026年10月 南京医科大学学报（自然科学版），2026，46（10）：1567-1583 ·1569 ·

Glutamine

Cytomembrane
SLC1A5

Glucose
Glutamine

ATP ATP

Cholesterol Pyruvate Lactate
synthesis

Acetyl⁃CoA
Aspartic acid GLS

Oxaloacetate Lipid
Citrate synthesis
TCA cycle
Succinyl⁃CoA GDH
Glutamic
α⁃KG
acid
GS

GSH

Extracellular Gln enters the cell via the membrane transporter SLC1A5 and is catalyzed by GLS to produce glutamate. Glu is then deaminated by
glutamate dehydrogenase to generate α⁃ketoglutarate，which enters the tricarboxylic acid cycle and subsequently undergoes oxidative phosphorylation to
produce ATP，thereby supplying energy for cellular processes. Intermediate products of the TCA cycle can be further converted into oxaloacetate，which
is catalyzed by GOT1 to produce aspartate，or together with acetyl ⁃ CoA，participate in cholesterol synthesis. Glu also serves as a precursor for
glutathione synthesis，working in concert with NADPH to maintain intracellular redox homeostasis. In addition，glucose is metabolized via glycolysis to
generate pyruvate，which can be either converted into lactate or enter mitochondria to produce acetyl⁃CoA for the TCA cycle. The red lightning bolt
symbols in the figure indicate steps corresponding to inhibitors that have entered clinical trials.
图1 谷氨酰胺代谢示意图
Figure 1 Schematic diagram of glutamine metabolism

接对抗化疗诱导的ROS爆发，为开发新的治疗策略 毒癌基因同源物（kirsten rat sarcoma viral oncogene
提供了潜在靶点。然而，不同恶性肿瘤对 Gln 代谢 homolog，KRAS）突变则通过 Hippo⁃YAP1 通路上调
的依赖环节和代偿策略存在显著差异（表 1），例 多种氨基酸转运体 ［11］ ；②微环境特征进一步调控代

13
如，C 示踪实验显示，TNBC 细胞内>50%的α⁃KG 谢可塑性，缺氧诱导因子（hypoxia⁃inducible factor，
来源于 Gln，且下游 TCA 循环代谢物 C 富集度显 HIF）激活糖酵解，高基质肿瘤中肿瘤相关成纤维细
13
著高于非 TNBC 亚型，首次从亚型水平证实 TNBC 胞（cancer⁃associated fibroblast，CAF）通过谷氨酰胺
对Gln⁃α⁃KG轴的高度依赖，同时提示不同癌症类 合成酶（glutamine synthetase，GS）分泌 Gln 形成代谢
型对 Gln 代谢依赖程度存在显著异质性 。这种 耦合，且免疫细胞浸润激活信号转导与转录激活因
［8］
异质性主要源于三重分子基础：①致癌驱动基因 子 3（signal transducer and activator of transcription 3，
决定代谢成瘾模式，骨髓细胞瘤病毒癌基因同源物 STAT3）⁃GLS1正反馈环 ［12］ ；③代谢基线同时影响靶
（myelocytomatosis concogene，MYC）扩增通过抑制 向敏感性，如异柠檬酸脱氢酶（isocitrate dehydr⁃
［10］
miR⁃23a/b 间接上调 GLS1 ，而 kirsten 大鼠肉瘤病 ogenase，IDH）野生型胶质母细胞瘤（glioblastoma，