Xanthine oxidoreductase (XOR) serves as the primary source of hydrogen peroxide and superoxide anions in the intestinal mucosa. However, its specific contribution to the progression of colonic disease 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 observed that XOR inhibitors, allopurinol and diphenyleneiodonium sulfate (DPI), significantly alleviated UC in mice. In addition, treatment with cobalt chloride (CoCl₂) and 1% O₂ increased the expression of XOR and induced DNA oxidative damage in colonic epithelial cells. Furthermore, we identified that XOR accumulation in the nucleus may directly cause DNA oxidative damage and regulates HIF1α protein levels. In addition, allopurinol effectively protected colon epithelial cells from CoCl₂-induced DNA damage. Altogether, our data provided 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).

黄嘌呤氧化还原酶（XOR）是肠粘膜中过氧化氢和超氧阴离子的主要来源。然而，其对结肠疾病进展的具体贡献仍不清楚。在这项研究中，我们研究了 XOR 在溃疡性结肠炎 (UC) 中的作用，并试图确定其潜在机制。我们使用葡聚糖硫酸钠 (DSS) 诱导的小鼠模型来模拟 UC，并观察到 ​​XOR 抑制剂、别嘌呤醇和硫酸二亚苯基碘鎓 (DPI) 显着减轻了小鼠的 UC。此外，用氯化钴(CoCl ₂ )和1% O ₂处理可增加结肠上皮细胞中XOR的表达并诱导DNA氧化损伤。此外，我们发现细胞核中的 XOR 积累可能直接引起 DNA 氧化损伤并调节 HIF1α 蛋白水平。此外，别嘌呤醇有效保护结肠上皮细胞免受CoCl ₂诱导的DNA损伤。总而言之，我们的数据提供了 XOR 在缺氧条件下可诱导 DNA 损伤的证据，表明 XOR 在结肠炎相关结直肠癌 (CAC) 的发生和早期发展中发挥着重要作用。