代谢重编程是肿瘤的基本特征之一，可能极大地促进癌症转移。采用基于液相色谱-串联质谱的代谢组学，我们分析了射波刀立体定向放射治疗前后 12 例 NSCLC 脑转移患者的两对血清样本的代谢谱。我们评估了 144 个手术切除的 NSCLC 脑转移瘤的组织病理学结构。筛选差异代谢物并进行功能聚类和注释。代谢组学分析确定了一条富含支链氨基酸 (BCAA) 代谢的途径。病理上，生长方式坚实的腺癌脑转移倾向较高。肺腺癌组织中BCAT1蛋白水平高的患者与不良预后相关。我们发现脑 NSCLC 细胞的 BCAA 分解代谢升高，从而导致 α-KG 的消耗。这种耗竭反过来又降低了 m6A 去甲基化酶 ALKBH5 的表达和活性。因此，抑制ALKBH5参与维持间充质基因的m6A甲基化，促进NSCLC细胞上皮间质转化（EMT）的发生和脑内NSCLC细胞的增殖。 BCAA 分解代谢在 NSCLC 细胞的转移中发挥着重要作用。© 作者。

Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.© The author(s).