O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma
Abstract 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. Ho...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02464-2 |
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| author | Sijia Fang Guoqing Zhu Yi Xie Miao Ding Ni Zhen Jiabei Zhu Siwei Mao Xiaochen Tang Han Wu Qi Zhang Aijia Zhang Xin Ni Qiuhui Pan Ji Ma |
| author_facet | Sijia Fang Guoqing Zhu Yi Xie Miao Ding Ni Zhen Jiabei Zhu Siwei Mao Xiaochen Tang Han Wu Qi Zhang Aijia Zhang Xin Ni Qiuhui Pan Ji Ma |
| author_sort | Sijia Fang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b3a7b66cafba489988bbda5d3b4652df |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-b3a7b66cafba489988bbda5d3b4652df2025-08-20T03:10:09ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111310.1038/s41420-025-02464-2O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastomaSijia Fang0Guoqing Zhu1Yi Xie2Miao Ding3Ni Zhen4Jiabei Zhu5Siwei Mao6Xiaochen Tang7Han Wu8Qi Zhang9Aijia Zhang10Xin Ni11Qiuhui Pan12Ji Ma13Clinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineBeijing 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)Clinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineClinical Laboratory, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41420-025-02464-2 |
| spellingShingle | Sijia Fang Guoqing Zhu Yi Xie Miao Ding Ni Zhen Jiabei Zhu Siwei Mao Xiaochen Tang Han Wu Qi Zhang Aijia Zhang Xin Ni Qiuhui Pan Ji Ma O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma Cell Death Discovery |
| title | O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| title_full | O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| title_fullStr | O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| title_full_unstemmed | O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| title_short | O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| title_sort | o glcnacylation of glutaminase isoform kga inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma |
| url | https://doi.org/10.1038/s41420-025-02464-2 |
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