肠上皮细胞（IEC）的铁死亡已被确定为溃疡性结肠炎（UC）发展的关键因素。因此，靶向抑制铁死亡可能为UC的治疗提供新策略。异鼠李素 (ISO) 是一种 O-甲基化黄酮醇，对多种疾病具有治疗作用，如心血管疾病、神经系统疾病和肿瘤。然而，ISO在铁死亡和相关结肠炎中的作用和机制却很少被研究。在这项研究中，我们证明 ISO 可以通过抑制 DSS 诱导的小鼠 IEC 铁死亡来有效缓解肠道炎症。此外，我们的结果表明，ISO 在多种人类和小鼠细胞系中充当有效且常见的铁死亡抑制剂。从机制上讲，ISO 抑制铁死亡的作用与其先前报道的靶点 MEK1 和 PI3K 无关，但通过靶向和激活 NRF2 减轻了氧化应激。此外，ISO还可以直接螯合铁以阻止铁死亡。总之，我们的研究表明 ISO 作为一种新型潜在的铁死亡抑制剂，为铁死亡相关结肠炎提供了一种有前景的治疗策略。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Ferroptosis of intestinal epithelial cells (IECs) had been identified as a key factor in the development of ulcerative colitis (UC). Therefore, targeted inhibition of ferroptosis may provide a new strategy for the treatment of UC. Isorhamnetin (ISO) was an O-methylated flavonol with therapeutic effects on a variety of diseases, such as cardiovascular disease, neurological disorders and tumors. However, the role and mechanism of ISO in ferroptosis and associated colitis were rarely investigated. In this study, we demonstrated that ISO could effectively alleviate intestinal inflammation by inhibiting ferroptosis of IECs in DSS-induced mice. Moreover, our results shown that ISO acted as a potent and common ferroptosis inhibitor in multiple human and murine cell lines. Mechanistically, ISO inhibited ferroptosis independent of its previously reported targets MEK1 and PI3K, but alleviated oxidative stress by targeting and activating NRF2. Furthermore, ISO could also directly chelate iron to hinder ferroptosis. In conclusion, our study indicated that ISO as a novel potential ferroptosis inhibitor, providing a promising therapeutic strategy for ferroptosis-related colitis.Copyright © 2024 Elsevier B.V. All rights reserved.