GCLM (glutamate-cysteine ligase modifier subunit) is a regulatory subunit of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione (GSH) biosynthesis 1. As part of the GCL complex, GCLM regulates the first committed step of GSH synthesis in the cytosol, functioning alongside the catalytic subunit GCLC 2. GSH is the most abundant non-protein thiol in mammalian tissues, serving critical roles in oxidative stress defense, xenobiotic detoxification, and redox signaling 1. GCLM expression is transcriptionally regulated by key oxidative stress-responsive transcription factors including Nrf2/NRF2 via antioxidant response elements 23. Beyond its canonical metabolic function, GCLM exhibits moonlighting activities: nuclear-translocated GCLM promotes chemoresistance in colorectal cancer by phosphorylation-dependent interaction with NF-κB pathway components 4. Post-translational modifications, including lactylation by ACAT2, enhance GCLM enzymatic activity and promote ferroptosis resistance in KRAS-mutant cancers 5. Dysregulation of GCLM-dependent GSH synthesis contributes to multiple pathological conditions including diabetes, liver fibrosis, and drug-resistant tumors 1. GCLM represents both a metabolic enzyme and a regulatory hub in cellular stress responses, making it a potential therapeutic target for cancer and degenerative diseases.