2. Academic Validation
  3. O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma

O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma

  • Cell Death Discov. 2025 Apr 9;11(1):160. doi: 10.1038/s41420-025-02464-2.
Sijia Fang # 1,  Guoqing Zhu # 1,  Yi Xie # 1,  Miao Ding 1,  Ni Zhen 1,  Jiabei Zhu 1,  Siwei Mao 1,  Xiaochen Tang 1,  Han Wu 1,  Qi Zhang 1,  Aijia Zhang 1,  Xin Ni 2 3,  Qiuhui Pan 4 5 6 7,  Ji Ma 8 9
Affiliations

Affiliations

  • 1 Clinical Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 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. nixin@bch.com.cn.
  • 3 Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China. nixin@bch.com.cn.
  • 4 Clinical Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. panqiuhui@scmc.com.cn.
  • 5 Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China. panqiuhui@scmc.com.cn.
  • 6 Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. panqiuhui@scmc.com.cn.
  • 7 Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center, Sanya, China. panqiuhui@scmc.com.cn.
  • 8 Clinical Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. maji@scmc.com.cn.
  • 9 Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China. maji@scmc.com.cn.
  • # Contributed equally.
PMID: 40204725 DOI: 10.1038/s41420-025-02464-2
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.

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