Li Yingping, Zhang Fenna, Hu Fumin, Tong Rui, Wen Yueqi, Fu Guokai, Bian Xueli
Department of Clinical Nutrition, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
The First Affiliated Hospital of Xi'an Medical University, Xi'an, China.
Cell Death Discov. 2025 Jun 4;11(1):266. doi: 10.1038/s41420-025-02544-3.
Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.
代谢可塑性维持胶质母细胞瘤（GBM）在营养应激下的存活，但果糖分解适应如何补偿葡萄糖剥夺尚不清楚。在这里，我们确定甘油酸激酶2（GLYCTK2）是一种葡萄糖感应代谢检查点，它通过ERK1介导的磷酸化维持GBM细胞活力。从机制上讲，葡萄糖剥夺激活的ERK1直接在丝氨酸220处磷酸化GLYCTK2，这阻止了STUB1（泛素E3连接酶）的结合，从而消除了GLYCTK2的泛素化和降解。重要的是，功能研究表明，补充果糖可挽救野生型GBM细胞中葡萄糖剥夺诱导的死亡，但无法保护GLYCTK2缺失的细胞，确立了GLYCTK2作为果糖分解挽救途径的守门人。这些发现证明了一种重要机制，即GBM细胞通过磷酸化和稳定GLYCTK2将葡萄糖代谢重编程为果糖代谢，以在葡萄糖剥夺条件下维持GBM细胞存活，强调了靶向GLYCTK2治疗GBM患者的潜力。
