STEAP3 is an integral membrane metalloreductase that plays crucial roles in cellular iron homeostasis and disease pathogenesis. The protein functions as a NADPH-dependent ferric-chelate reductase, facilitating transferrin-dependent iron uptake by reducing Fe(3+) to Fe(2+) and can also reduce Cu(2+) to Cu(1+) 1. STEAP3 contains six transmembrane domains and mediates sequential electron transfer from NADPH through FAD and heme to metal chelates. In disease contexts, STEAP3 demonstrates significant clinical relevance across multiple conditions. Genetic variants in STEAP3 are associated with red blood cell storage quality and hemolysis, with polymorphisms affecting iron content and lipid peroxidation in blood donors 2. The protein serves protective functions in ischemia/reperfusion lung injury by alleviating iron overload and reducing inflammation through inhibition of NF-κB and TGFβ1/SMAD signaling pathways 3. However, STEAP3 also promotes cancer progression, particularly in triple-negative breast cancer where it facilitates copper accumulation and activates the CDK16-JAK1 pathway, enhancing cell proliferation and metastasis 4. Additionally, STEAP3 variants are identified as hepatocellular carcinoma susceptibility genes 5. These findings establish STEAP3 as a critical regulator of metal homeostasis with both protective and pathogenic roles depending on cellular context.