Ulcerative colitis (UC) is a disease characterized by inflammation and disruption of the intestinal epithelial barrier. Necroptosis plays a critical role in disease progression. Indole-3-carbinol (I3C), a natural dietary agonist of aryl hydrocarbon receptor (AHR), has shown alleviating effects on UC. However, its mechanisms of action have not been comprehensively elucidated. Therefore, we aimed at investigating the protective role of I3C in DSS-induced colitis mice models. I3C significantly ameliorated body weight loss, colon length shortening and colonic pathological damage in colitis mice, reduced disease activity index (DAI) and histological (HI) scores, as well as alleviated colonic necroptosis and inflammation. In vitro, I3C attenuated necroptosis and inflammation of colonoids and NCM460 cells. AHR, activated by I3C, inhibits activation of receptor-interacting protein kinase 1 (RIPK1) and the subsequent assembly of necrosome in a time-dependent manner, as well as suppressing NF-κB activation and decreasing TNF-α, IL-1β, IL-6 and IL-8 expression. Silencing of AHR aggravated necroptosis and inflammation of NCM460 cells, and did not be ameliorated by I3C. Furthermore, AHR activation induces the expression of inhibitor of apoptosis proteins (IAPs) and the ubiquitination of RIPK1. In conclusion, I3C exerts a protective effect in DSS-induced colitis mice models by alleviating the necroptosis and inflammation of IECs through activating AHR.

溃疡性结肠炎 (UC) 是一种以炎症和肠上皮屏障破坏为特征的疾病。坏死性凋亡在疾病进展中起着关键作用。Indole-3-carbinol (I3C) 是一种天然的芳烃受体 (AHR) 膳食激动剂，已显示出对 UC 的缓解作用。但其作用机制尚未完全阐明。因此，我们旨在研究 I3C 在 DSS 诱导的结肠炎小鼠模型中的保护作用。I3C 显着改善结肠炎小鼠的体重减轻、结肠长度缩短和结肠病理损伤，降低疾病活动指数 (DAI) 和组织学 (HI) 评分，以及减轻结肠坏死和炎症。在体外，I3C 减弱了结肠和 NCM460 细胞的坏死性凋亡和炎症。AHR，由 I3C 激活，以时间依赖性方式抑制受体相互作用蛋白激酶 1 (RIPK1) 的激活和随后的坏死体组装，以及抑制 NF-κB 激活和降低 TNF-α、IL-1β、IL-6 和 IL-8表达。AHR 的沉默加剧了 NCM460 细胞的坏死性凋亡和炎症，并且没有被 I3C 改善。此外，AHR 激活诱导凋亡蛋白抑制剂 (IAP) 的表达和 RIPK1 的泛素化。总之，I3C 通过激活 AHR 减轻 IEC 的坏死性凋亡和炎症，从而在 DSS 诱导的结肠炎小鼠模型中发挥保护作用。AHR 的沉默加剧了 NCM460 细胞的坏死性凋亡和炎症，并且没有被 I3C 改善。此外，AHR 激活诱导凋亡蛋白抑制剂 (IAP) 的表达和 RIPK1 的泛素化。总之，I3C 通过激活 AHR 减轻 IEC 的坏死性凋亡和炎症，从而在 DSS 诱导的结肠炎小鼠模型中发挥保护作用。AHR 的沉默加剧了 NCM460 细胞的坏死性凋亡和炎症，并且没有被 I3C 改善。此外，AHR 激活诱导凋亡蛋白抑制剂 (IAP) 的表达和 RIPK1 的泛素化。总之，I3C 通过激活 AHR 减轻 IEC 的坏死性凋亡和炎症，从而在 DSS 诱导的结肠炎小鼠模型中发挥保护作用。