Glutathione synthetase (GSS) catalyzes the ATP-dependent synthesis of glutathione from gamma-glutamylcysteine and glycine, producing the most abundant intracellular thiol required for cellular protection against oxidative damage, xenobiotic detoxification, and maintenance of protein redox state. GSS also participates in ophthalmate biosynthesis in hepatocytes. Pathogenic variants in GSS cause glutathione synthetase deficiency, a rare autosomal recessive disorder with variable severity. Affected individuals present with hemolytic anemia, neurological manifestations, and metabolic abnormalities including 5-oxoprolinuria in some cases. At the population level, gnomAD v4.1 classifies this gene as loss-of-function tolerant (LOEUF=0.82) because heterozygous carriers are viable; this is distinct from clinical pathogenicity observed in biallelic disease carriers, who accumulate 54 pathogenic or likely pathogenic ClinVar variants. Recent evidence suggests GSS dysfunction contributes to ferroptosis resistance in hepatocellular carcinoma. A 2025 study proposed that the regulatory axis miR-30a-5p/RRM2/GSS modulates glutathione synthesis and ferroptosis susceptibility, positioning GSS as a potential target for ferroptosis-dependent therapies in drug-resistant hepatocellular carcinoma 1.