转酰胺酶2 (TG2) 参与多种细胞内酶的后转录修饰，对癌症的发病和进展起到影响作用。我们使用1 H-NMR 代谢组学研究了一种新型的TG2 抑制剂 AA9 对两种具有不同表型的乳腺癌细胞系 MCF-7 和 MDA-MB-231 的影响。AA9 能够促进两种细胞系中的凋亡，但在 MD-MB-231 细胞系中特别有效，抑制酰胺转移反应，降低细胞迁移和浸润能力。这种代谢组学研究提供了AA9 对 MDA-MB-231 细胞的重大影响证据，对谷氨酸和天冬氨酸代谢有影响，而 MCF-7 细胞则表现为胆碱和O-磷酸胆碱的降低。有趣的是，AA9 治疗在两种细胞系中诱导了肌醇的变化，表明其对磷脂酰肌醇代谢的作用，可能受到 TG2 对磷脂酰肌醇酶 C 的 G 蛋白调控的影响。考虑到其特征性的乳腺癌亚型代谢失调情况，AA9 影响的代谢途径进一步说明了 TG2 作为一个有前途的热点。代谢组学方法为监测抑制剂的有效性和更好地理解 TG2 在癌症中的作用提供了有力工具。本文受版权保护。保留所有权利。

Transglutaminase 2 (TG2), mediating post-translational modifications of multiple intracellular enzymes, is involved in the pathogenesis and progression of cancer. We used 1 H-NMR metabolomics to study the effects of AA9, a novel TG2 inhibitor, on two breast cancer cell lines with distinct phenotypes, MCF-7 and MDA-MB-231. AA9 can promote apoptosis in both cell lines, but it is particularly effective in MD-MB-231, inhibiting transamidation reactions and decreasing cell migration and invasiveness. This metabolomics study provides evidence of a major effect of AA9 on MDA-MB-231 cells, impacting glutamate and aspartate metabolism, rather than on MCF-7 cells, characterized by choline and O-phosphocholine decrease. Interestingly, AA9 treatment induces myo-inositol alteration in both cell lines, indicating action on phosphatidylinositol metabolism, likely modulated by the G-protein activity of TG2 on phospholipase C. Considering the metabolic deregulations that characterize various breast cancer subtypes, the existence of a metabolic pathway affected by AA9 further points to TG2 as a promising hot spot. The metabolomics approach provides a powerful tool to monitor the effectiveness of inhibitors and to better understand the role of TG2 in cancer.This article is protected by copyright. All rights reserved.