Glutathione (GSH) is a crucial intracellular antioxidant and detoxifying molecule found in all mammalian cells, especially in the liver. It exists in two forms: reduced (GSH) and oxidized (GSSG). GSH is synthesized in the cytosol through two enzymatic steps, catalyzed by glutamate cysteine ligase (GCL) and GSH synthase (GS). GCL, composed of GCLC and GCLM subunits, is the rate-limiting enzyme in GSH synthesis and is regulated by cysteine availability and its activity. GSH synthase (GS) is also regulated and can enhance GSH synthesis when up-regulated. Oxidative stress induces GSH synthesis enzymes, with key transcription factors including Nrf2, AP-1, and NFκB. Dysregulation of GSH synthesis contributes to various diseases, including diabetes, pulmonary fibrosis, and liver injury. GSH functions in detoxification, antioxidant defense, maintaining thiol status, and modulating cell proliferation and death. It also serves as a cysteine storage and is involved in the γ-glutamyl cycle. GSH synthesis is regulated by factors such as diet, methionine metabolism, and the transsulfuration pathway. GCL activity is regulated at multiple levels, including transcriptional and post-transcriptional mechanisms, with Nrf2, AP-1, and NFκB playing key roles. GCLM, the modifier subunit, also regulates GCL activity and is influenced by oxidative stress and other factors. GSH synthase (GS) is involved in GSH synthesis and is regulated by various conditions, including oxidative stress and antioxidant treatments. Overall, GSH synthesis is a complex process regulated by multiple factors, and its dysregulation can lead to various pathological conditions.Glutathione (GSH) is a crucial intracellular antioxidant and detoxifying molecule found in all mammalian cells, especially in the liver. It exists in two forms: reduced (GSH) and oxidized (GSSG). GSH is synthesized in the cytosol through two enzymatic steps, catalyzed by glutamate cysteine ligase (GCL) and GSH synthase (GS). GCL, composed of GCLC and GCLM subunits, is the rate-limiting enzyme in GSH synthesis and is regulated by cysteine availability and its activity. GSH synthase (GS) is also regulated and can enhance GSH synthesis when up-regulated. Oxidative stress induces GSH synthesis enzymes, with key transcription factors including Nrf2, AP-1, and NFκB. Dysregulation of GSH synthesis contributes to various diseases, including diabetes, pulmonary fibrosis, and liver injury. GSH functions in detoxification, antioxidant defense, maintaining thiol status, and modulating cell proliferation and death. It also serves as a cysteine storage and is involved in the γ-glutamyl cycle. GSH synthesis is regulated by factors such as diet, methionine metabolism, and the transsulfuration pathway. GCL activity is regulated at multiple levels, including transcriptional and post-transcriptional mechanisms, with Nrf2, AP-1, and NFκB playing key roles. GCLM, the modifier subunit, also regulates GCL activity and is influenced by oxidative stress and other factors. GSH synthase (GS) is involved in GSH synthesis and is regulated by various conditions, including oxidative stress and antioxidant treatments. Overall, GSH synthesis is a complex process regulated by multiple factors, and its dysregulation can lead to various pathological conditions.