2. Academic Validation
  3. Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells

Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells

  • Cell Prolif. 2025 Apr 21:e70036. doi: 10.1111/cpr.70036.
Changsen Bai 1 2,  Jialei Hua 1,  Donghua Meng 3,  Yue Xu 4,  Benfu Zhong 5,  Miao Liu 6,  Zhaosong Wang 7,  Wei Zhou 1,  Liming Liu 8,  Hailong Wang 4,  Yang Liu 9 10,  Lifang Li 4,  Xiuju Chen 11,  Yueguo Li 1
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 2 Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China.
  • 3 Department of Radiology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 4 Department of Cancer Cell Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 5 Department of Pediatric Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 6 Department of Radiotherapy, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 7 Laboratory Animal Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 8 Department of Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 9 Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 10 Department of Hepatobiliary and Pancreatic Oncology, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
  • 11 Department of Neurology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China.
PMID: 40259435 DOI: 10.1111/cpr.70036
Abstract

Glutaminase-1 (GLS1) has garnered considerable interest as a metabolic target in Cancer due to its heightened involvement and activity. However, the precise fate of glutaminolysis catalysed by GLS1 in Cancer cells remains elusive. We found that GLS1 knockout led to significant suppression of Cancer cell proliferation, which can be reversed or partially restored by supplementation of glutamate or non-essential Amino acids that can be converted into glutamate. The addition of spliceosomal KGA or GAC ameliorates Cancer cell growth in vitro and in vivo, providing both simultaneously completely reverse the effect. The primary metabolic fate of glutamate produced through glutaminolysis in Cancer cells is mainly used to produce glutathione (GSH) for redox homeostasis, not entering the tricarboxylic acid cycle or synthesising nucleotides. GSH monoethyl ester (GSH-MEE) effectively rescues the inhibition of Cancer cell proliferation caused by GLS1 knockout. Deletion of GLS1 results in an elevation of Reactive Oxygen Species (ROS) and malondialdehyde (MDA), a reduction of NADPH/NADP+ ratio, and an augmented susceptibility of cells to Ferroptosis. Glutathione Peroxidase 4 (GPX4) and GPX1 exhibit complementary roles in redox regulation, with GLS1 knockout promoting GPX4 degradation. Pharmacological inhibition of GLS1 synergises with GPX4 inhibitor to suppress tumour growth. Dual targeting of GPX4 and GPX1 presents a potent anti-cancer strategy. This metabolic mechanism facilitates a deeper comprehension of the abnormal glutamine metabolism in Cancer cells, establishing a theoretical basis for the potential clinical utilisation of GLS1 inhibitors and presenting novel perspectives for advancing combinatorial therapeutic approaches.

Keywords

GLS1; GPX4; GSH; cancer cell; ferroptosis; glutamate.

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