GCLC (glutamate-cysteine ligase catalytic subunit) catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine, catalyzing the first and rate-limiting step of glutathione (GSH) biosynthesis 1. As the catalytic component of the glutamate-cysteine ligase complex, GCLC works coordinately with its modifier subunit GCLM to maintain intracellular GSH levels 2. GSH is the most abundant non-protein thiol in mammalian tissues, serving critical functions in antioxidant defense, detoxification of xenobiotics, redox signaling, and regulation of cell proliferation and apoptosis 1. GCLC expression is regulated by multiple transcription factors including Nrf2 via antioxidant response elements, AP-1, and NFκB, with upregulation occurring during oxidative stress 2. Beyond canonical GSH synthesis, GCLC possesses a non-canonical activity producing γ-glutamyl-peptides that protect against ferroptosis by maintaining glutamate homeostasis during cysteine limitation 3. GCLC expression is dysregulated in various cancers, where enhanced GSH synthesis promotes chemoresistance and ferroptosis resistance through histone lactylation, NSUN2-mediated mechanisms, and cuproptosis resistance pathways 456. Clinically, GCLC mutations cause congenital non-spherocytic hemolytic anemia 1. Dysregulation of GCLC-dependent GSH synthesis contributes to pathogenesis of diabetes, pulmonary and liver fibrosis, alcoholic liver disease, and viral infections including H1N1 influenza 17.