Glutathione synthetase (GSS) catalyzes the ATP-dependent synthesis of glutathione (GSH) from gamma-glutamylcysteine and glycine 12. GSH is the most abundant intracellular thiol in aerobic cells and serves critical protective functions, including defense against oxidative damage, amino acid transport, detoxification of xenobiotics, maintenance of protein disulfide bonds, and enzymatic cofactor activity 3. GSS participates in ophthalmate biosynthesis in hepatocytes and is predominantly localized to the cytosol. Loss-of-function mutations in GSS cause glutathione synthetase deficiency, manifesting as congenital non-spherocytic hemolytic anemia 3. Recent evidence indicates GSS plays a critical role in ferroptosis resistance in hepatocellular carcinoma; the regulatory axis HCG18/miR-30a-5p/RRM2/GSS controls GSH synthesis and confers resistance to ferroptosis-inducing agents, suggesting GSS as a potential therapeutic target in drug-resistant cancers 4. The enzyme's central role in antioxidant metabolism makes it essential for cellular stress response and redox homeostasis, with dysregulation implicated in both genetic disorders and malignant disease progression.