GSR (glutathione-disulfide reductase) is a key antioxidant enzyme that catalyzes the reduction of oxidized glutathione (GSSG) to its reduced form (GSH), maintaining the high GSH:GSSG ratio essential for cellular redox homeostasis 1. Located on chromosome 8, GSR functions primarily in the cytosol and mitochondria, utilizing NADPH as an electron donor to support cellular antioxidant defense 2. Mechanistically, GSR depletion reduces intracellular GSH levels, leading to reactive oxygen species (ROS) accumulation and activation of oxidative stress pathways, including the TGF-β/Smad2 signaling cascade 1. GSR function is regulated by zinc binding to cysteine residues, providing an additional layer of post-translational control 3. Hereditary GSR deficiency, caused by autosomal recessive mutations, results in decreased GSSG reduction capacity and thermal instability, with specific SNPs linked to hereditary anemia and obstructive heart defects 4. Clinically, GSR loss occurs frequently in lung cancers (25-50% of adenocarcinomas and squamous cell carcinomas), serving as a potential predictive biomarker for precision therapy 2. In idiopathic pulmonary fibrosis, GSR downregulation exacerbates disease progression by impairing epithelial-to-mesenchymal transition control and fibroblast activation 1. Additionally, GSR inhibition enhances sorafenib efficacy in hepatocellular carcinoma by promoting ferroptotic cell death 5, suggesting therapeutic potential for GSR-targeting strategies in cancer treatment.