Glutathione (GSH) is a critical antioxidant in cancer progression and treatment resistance. It maintains cellular redox homeostasis, detoxifies xenobiotics, and protects cancer cells from chemotherapy. However, GSH metabolism has dual roles in cancer, influencing cell survival and tumor progression. Elevated GSH levels in cancer cells enhance resistance to chemotherapeutic agents and promote metastasis. GSH also plays a role in oxidative stress and cancer initiation, with both ROS and GSH contributing to tumor development. GSH synthesis is regulated by enzymes such as glutamate cysteine ligase (GCL) and GSH synthetase (GSS), with GCL being a key rate-limiting step. GSH levels are influenced by factors like cysteine availability, NADPH production, and the NRF2-KEAP1 pathway. GSH is involved in detoxification, maintaining cysteine pools, and regulating transcription factors. GSH also supports mitochondrial function and prevents apoptosis. GSH metabolism is crucial for cancer cell survival, and targeting GSH synthesis or utilization can increase sensitivity to chemotherapy and radiotherapy. GSH is also involved in the γ-glutamyl cycle, which provides cysteine for GSH synthesis. GSH levels are regulated by transporters like xCT, which import cystine. Inhibiting GSH synthesis or utilization can enhance the effectiveness of cancer therapies. The NRF2-KEAP1 pathway regulates GSH production, and its dysregulation is associated with cancer progression. GST enzymes contribute to drug resistance by conjugating xenobiotics with GSH. Targeting GSH metabolism is a promising strategy for improving cancer treatment outcomes.Glutathione (GSH) is a critical antioxidant in cancer progression and treatment resistance. It maintains cellular redox homeostasis, detoxifies xenobiotics, and protects cancer cells from chemotherapy. However, GSH metabolism has dual roles in cancer, influencing cell survival and tumor progression. Elevated GSH levels in cancer cells enhance resistance to chemotherapeutic agents and promote metastasis. GSH also plays a role in oxidative stress and cancer initiation, with both ROS and GSH contributing to tumor development. GSH synthesis is regulated by enzymes such as glutamate cysteine ligase (GCL) and GSH synthetase (GSS), with GCL being a key rate-limiting step. GSH levels are influenced by factors like cysteine availability, NADPH production, and the NRF2-KEAP1 pathway. GSH is involved in detoxification, maintaining cysteine pools, and regulating transcription factors. GSH also supports mitochondrial function and prevents apoptosis. GSH metabolism is crucial for cancer cell survival, and targeting GSH synthesis or utilization can increase sensitivity to chemotherapy and radiotherapy. GSH is also involved in the γ-glutamyl cycle, which provides cysteine for GSH synthesis. GSH levels are regulated by transporters like xCT, which import cystine. Inhibiting GSH synthesis or utilization can enhance the effectiveness of cancer therapies. The NRF2-KEAP1 pathway regulates GSH production, and its dysregulation is associated with cancer progression. GST enzymes contribute to drug resistance by conjugating xenobiotics with GSH. Targeting GSH metabolism is a promising strategy for improving cancer treatment outcomes.