支链α-酮酸脱氢酶激酶（BCKDK）是参与支链氨基酸（BCAA）代谢的关键酶。它作为多种癌症的治疗靶点和预后因素的潜力已被广泛报道。在本研究中，我们调查了临床胶质瘤样本中 BCKDK 的表达，发现 BCKDK 在胶质母细胞瘤（GBM）中显着过表达，并与其不良预后相关。我们进一步发现BCKDK被酪氨酸蛋白激酶Fyn在Y151位点磷酸化，从而增加了其催化活性和稳定性，并通过体内和体外实验证明BCKDK磷酸化促进GBM细胞增殖。此外，我们发现高BCKDK的GBM细胞中代谢物N-乙酰-L-丙氨酸（NAAL）的水平高于沉默组，并且BCKDK的沉默或抑制会促进ACY1酶的表达催化 NAAL 水解成乙酸和丙氨酸。外源添加NAAL可激活ERK信号通路，促进GBM细胞增殖。综上所述，我们确定了 BCKDK 激活的新机制，并发现 NAAL 是一种新的致癌代谢物。我们的研究证实了 Fyn-BCKDK-ACY1-NAAL 信号轴在 GBM 发展中的重要性，并表明 p-BCKDK (Y151) 和 NAAL 可以作为 GBM 进展和预后的潜在预测因子。© 2024 作者。

Branched chain α-keto acid dehydrogenase kinase (BCKDK) is a key enzyme involved in the metabolism of branched-chain amino acids (BCAAs). Its potential as a therapeutic target and prognostic factor for a variety of cancers has been widely reported. In this study, we investigated the expression of BCKDK in clinical glioma samples and found that BCKDK was significantly overexpressed in glioblastoma (GBM) and was associated with its poor prognosis. We further found that BCKDK is phosphorylated by tyrosine protein kinase Fyn at Y151, which increases its catalytic activity and stability, and demonstrate through in vivo and in vitro experiments that BCKDK phosphorylation promotes GBM cell proliferation. In addition, we found that the levels of the metabolite N-acetyl-L-alanine (NAAL) in GBM cells with high BCKDK were higher than those in the silencing group, and silencing or inhibition of BCKDK promotes the expression of ACY1, an enzyme that catalyzes the hydrolysis of NAAL into acetic acid and alanine. Exogenous addition of NAAL can activate the ERK signaling pathway and promote the proliferation of GBM cells. Taken together, we identified a novel mechanism of BCKDK activation and found NAAL is a novel oncogenic metabolite. Our study confirms the importance of the Fyn-BCKDK-ACY1-NAAL signalling axis in the development of GBM and suggests that p-BCKDK (Y151) and NAAL can serve as potential predictors of GBM progression and prognosis.© 2024 The Authors.