DUOX2 (dual oxidase 2) is a hydrogen peroxide-generating NADPH oxidase essential for thyroid hormone synthesis and mucosal immunity. Functionally, DUOX2 produces H2O2 required for thyroid peroxidase activity in thyroid hormone synthesis 1 and supports lactoperoxidase-mediated antimicrobial defense at mucosal surfaces 2. DUOX2 also synthesizes NAADP to promote calcium signaling during T cell activation 3. Mechanistically, DUOX2 operates through hydrogen peroxide biosynthesis and superoxide generation via its NAD(P)H oxidase activity, localized to apical plasma membranes and extracellular compartments. Clinically, DUOX2 mutations are the leading genetic cause of congenital hypothyroidism (CH) in Chinese populations, present in 21-35% of cases 45. DUOX2 biallelic mutations predominantly cause dyshormonogenesis-related CH with goiter phenotype 6, and residual enzymatic activity ≤22% correlates with more severe hypothyroidism 7. Beyond thyroid disease, DUOX2 variants associate with inflammatory bowel disease risk through disrupted microbiota-immune homeostasis and elevated IL-17C 8. Additionally, DUOX2+ cholangiocytes are pathogenic targets in primary biliary cholangitis 9, and DUOX2 expression elevation via cGAS-STING activation promotes pancreatic cancer progression 10. DUOX2 emerges as both a therapeutic target and diagnostic biomarker across multiple inflammatory and neoplastic conditions.