Fang Sijia, Zhu Guoqing, Xie Yi, Ding Miao, Zhen Ni, Zhu Jiabei, Mao Siwei, Tang Xiaochen, Wu Han, Zhang Qi, Zhang Aijia, Ni Xin, Pan Qiuhui, Ma Ji
Clinical Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China.
Cell Death Discov. 2025 Apr 9;11(1):160. doi: 10.1038/s41420-025-02464-2.
Hepatoblastoma (HB), the most common pediatric hepatic malignancy, exhibits an increasing incidence. Metabolism reprogramming represents a pivotal hallmark in the oncogenic transformation process, with glutamine emerging as a critical energy source for neoplastic cells, rivaling glucose. However, the mechanism by which glutamine is involved in the development of HB remains unclear. Our study identified glutamine metabolism as a crucial factor in the development of HB. The key enzyme of glutamine metabolism, kidney-type glutaminase (GLS1), is activated in HB and regulates cell proliferation. Mechanistically, the GLS1 subtype KGA, utilizing glutamate derived from glutaminolysis, enhances glutathione (GSH) synthesis, which in turn inhibits ferroptosis in HB cells. Importantly, the Thr563 residue of KGA undergoes O-GlcNAcylation, enhancing enzyme activity and stability, accelerating glutaminolysis, and promoting the proliferation of HB. This study demonstrated that enhanced glutaminolysis, driven by GLS1, is crucial for the development of HB by inhibiting ferroptosis. The O-GlcNAcylation of KGA isoform ensures its stability and glutaminase function in HB cells, which can serve as a promising therapeutic target for KGA-mediated glutaminolysis in HB.
肝母细胞瘤（HB）是最常见的儿童肝脏恶性肿瘤，其发病率呈上升趋势。代谢重编程是致癌转化过程中的一个关键标志，谷氨酰胺成为肿瘤细胞的关键能量来源，可与葡萄糖相媲美。然而，谷氨酰胺参与HB发生发展的机制仍不清楚。我们的研究确定谷氨酰胺代谢是HB发生发展的一个关键因素。谷氨酰胺代谢的关键酶——肾型谷氨酰胺酶（GLS1）在HB中被激活并调节细胞增殖。机制上，GLS1亚型KGA利用谷氨酰胺分解产生的谷氨酸增强谷胱甘肽（GSH）合成，进而抑制HB细胞中的铁死亡。重要的是，KGA的苏氨酸563残基发生O-连接的N-乙酰葡糖胺糖基化（O-GlcNAcylation），增强酶活性和稳定性，加速谷氨酰胺分解，并促进HB的增殖。本研究表明，由GLS1驱动的谷氨酰胺分解增强通过抑制铁死亡对HB的发生发展至关重要。KGA亚型的O-GlcNAcylation确保其在HB细胞中的稳定性和谷氨酰胺酶功能，这可作为HB中KGA介导的谷氨酰胺分解的一个有前景的治疗靶点。
