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

• DOI: 10.1111/cpr.70036
• Publication Date: 2025-04-22T03:35:21Z
• Authors: Changsen Bai; Jialei Hua; Donghua Meng; Yue Xu; Benfu Zhong; Miao Liu; Zhaosong Wang; Wei Zhou; Liming Liu; Hailong Wang; Yang Liu; Lifang Li; Xiuju Chen; Yueguo Li
• Keywords: Glutaminolysis; Glutaminase; GPX1; GPX4

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 cells remains elusive. We found that knockout led significant suppression cell proliferation, which can be reversed or partially restored supplementation glutamate non‐essential amino acids converted into glutamate. The addition spliceosomal KGA GAC ameliorates growth vitro vivo, providing both simultaneously completely reverse effect. primary produced through is mainly used produce glutathione (GSH) for redox homeostasis, not entering tricarboxylic acid cycle synthesising nucleotides. GSH monoethyl ester (GSH‐MEE) effectively rescues inhibition proliferation caused knockout. Deletion results an elevation reactive oxygen species (ROS) malondialdehyde (MDA), reduction NADPH/NADP + ratio, augmented susceptibility ferroptosis. Glutathione Peroxidase 4 (GPX4) GPX1 exhibit complementary roles regulation, with promoting GPX4 degradation. Pharmacological synergises inhibitor suppress tumour growth. Dual targeting presents potent anti‐cancer strategy. This mechanism facilitates deeper comprehension abnormal glutamine metabolism cells, establishing theoretical basis potential clinical utilisation inhibitors presenting novel perspectives advancing combinatorial therapeutic approaches.