南方科技大学医学院陈国安研究组报道了沉默GGH通过增加叶酸应激和NADH的产生诱导自噬。相关论文于2025年4月23日发表于国际顶尖学术期刊《分子细胞生物学报》杂志上。

在本研究中，课题组研究人员发现GGH在肺腺癌中是一个至关重要的致癌基因。重要的是，该研究团队发现GGH沉默通过叶酸代谢和叶酸代谢物烟酰胺腺嘌呤二核苷酸（NADH）引起的叶酸应激升高诱导细胞自噬和自噬细胞死亡。通过增加NADH/NAD⁺比值，沉默GGH通过激活LKB1和CAMKK2激活AMPK，并提高AMP/ATP和ADP/ATP比值，从而触发早期自噬的启动，最终导致自噬细胞死亡。综上所述，他们的研究表明，GGH不仅可以作为预后标志物，还可以在早期自噬的启动中发挥关键作用。针对GGH调节叶酸代谢和NADH/NAD⁺比例的干预措施可能具有转化为人类癌症精准治疗的潜力。

据介绍，代谢紊乱和自噬之间有着不可分割的联系。γ -谷氨酰水解酶（GGH）是一种溶酶体糖蛋白，通过催化多谷氨酰叶酸水解成可运输的单谷氨酸来减少细胞内叶酸应激。叶酸代谢（包括叶酸代谢酶GGH）与自噬之间的关系鲜有报道。

附：英文原文

Title: Silencing GGH induces autophagy by increasing folate stress and production of NADH

Author: Li, Yu, Du, Yuhui, Chen, Sijie, Xie, Zhangrong, Li, Xinrui, Lin, Baoyue, Zhou, Zhiqing, Zhao, Huijie, Chen, Guoan

Issue&Volume: 2025-04-23

Abstract: There is an inextricable link between metabolic disorders and autophagy. Gamma-glutamyl hydrolase (GGH) is a lysosomal glycoprotein that reduces intracellular folate stress by catalyzing the hydrolysis of polyglutamylated folate into transportable monoglutamate. The relationship between folate metabolism, involving the folate metabolic enzyme GGH, and autophagy has rarely been reported. In this study, we found that GGH functions as a crucial oncogene in lung adenocarcinomas. Importantly, we found that cell autophagy and autophagic cell death are induced by GGH silencing through the elevated folate stress resulting from folate metabolism and the folate metabolite nicotinamide adenine dinucleotide (NADH). By increasing the NADH/NAD + ratio, silencing GGH activates AMPK through the activation of LKB1 and CAMKK2, as well as enhanced AMP/ATP and ADP/ATP ratios, which then triggers the initiation of early autophagy, finally resulting in autophagic cell death. Taken together, our study suggests that GGH may not only serve as a prognostic marker but also play a critical role in the initiation of early autophagy. Interventions targeting GGH to regulate folate metabolism and the proportion of NADH/NAD + may have translational potential for precision therapy in human cancer.

DOI: 10.1093/jmcb/mjaf014

Source: https://dx.doi.org/10.1093/jmcb/mjaf014