Hypoxia-mediated upregulation of xanthine oxidoreductase causes DNA damage of colonic epithelial cells in colitis

Abstract Xanthine oxidoreductase (XOR) is the primary source of hydrogen peroxide and superoxide anions in the intestinal mucosa. However, its specific contribution to the colonic disease progression remains unclear. In this study, we investigated the role of XOR in ulcerative colitis (UC) and attempted to identify the underlying mechanisms. We used the dextran sulfate sodium (DSS)-induced mouse model to mimic UC and found that the XOR inhibitors (allopurinol and diphenyleneiodonium sulfate (DPI) significantly alleviated UC in mice. Also, cobalt chloride (CoCl 2 ) and 1% O 2 treatment increases the expression of XOR and caused DNA oxidative damage in colonic epithelial cells. Furthermore, we found that XOR accumulated in the nucleus may directly cause DNA oxidative damage and regulates HIF1α protein levels. In addition, allopurinol effectively protected colon epithelial cells from CoCl 2 -induced DNA damage. Altogether, our data provide new evidence that XOR could induce DNA damage under hypoxic conditions indicating a significant role of XOR in the initiation and early development of colitis-associated colorectal cancer (CAC).