DUOX2, Dual Oxidase 2, is a key enzyme involved in the production of hydrogen peroxide, which plays crucial roles in various biological processes. It participates in innate defense responses, such as in the gut-epithelial innate defense where it releases hydrogen peroxide [2]. It is also involved in the organic process of thyroid hormone iodine [6].

In congenital hypothyroidism (CH), DUOX2 is the most frequently mutated gene in the Chinese population. Biallelic and triple variants of DUOX2 are common in children with thyroid dysgenesis (TD) and gland-in-situ (GIS), types of CH. The residual enzymatic activity of DUOX2 is closely related to the clinical phenotypes of CH patients caused by DUOX2 biallelic mutations, with 22% residual activity potentially being a cutoff for estimating hypothyroidism severity [1,3]. In inflammatory bowel disease (IBD), rare loss-of-function variants of DUOX2 are associated with increased plasma levels of interleukin-17C, a preclinical sign of disturbed microbiota-immune homeostasis [2]. In colitis-associated neoplasia, activation of epithelial TLR4 up-regulates DUOX2, which mediates the production of epithelial hydrogen peroxide, promoting tumorigenesis [4]. In pancreatic and colorectal cancers, DUOX2 promotes cell motility, proliferation, invasion, and metastasis. In pancreatic cancer, high DUOX2 expression is an independent prognostic indicator, and in colorectal cancer, it regulates the AKT pathway and interacts with RPL3 to facilitate cancer cell progression [5,6].

In conclusion, DUOX2 is essential for innate defense, thyroid hormone synthesis, and has significant impacts on multiple disease conditions. Studies using gene-knockout or other loss-of-function models have revealed its role in CH, IBD, colitis-associated neoplasia, and cancers, providing insights into disease mechanisms and potential therapeutic targets.