铁死亡与炎症性肠病的研究进展

doi:10.12114/j.issn.1007-9572.2022.0698

摘要/Abstract

摘要： 炎症性肠病（IBD）是一组慢性非特异性胃肠道炎症性疾病，其病因和发病机制可能与环境、基因易感性、肠道微生物群和免疫反应相关。铁死亡是近年来发现的一种铁依赖的脂质氢过氧化物累积所致的细胞死亡，受到包括谷胱甘肽（GSH）和谷胱甘肽过氧化物酶4（GPx4）的脂质修复系统的严密调控。研究表明，IBD患者受损的肠道可表现出铁沉积、GSH耗竭、GPx4失活和脂质过氧化（LPO）等铁死亡的基本特征。此外，操纵铁死亡的关键基因可以改变IBD的进展、严重程度甚至发病率。本文概述了铁死亡的基本机制，并就近年来铁死亡的相关信号通路在IBD中的研究展望予以综述，总结出铁死亡可通过外源性（转运蛋白依赖途径）和内源性（酶调控途径）途径启动，从而调控IBD，为未来临床IBD的治疗提供新方向。

关键词: 炎症性肠病, 铁死亡, 活性氧, 脂质过氧化作用, 治疗, 综述

Abstract:

Inflammatory bowel disease (IBD) is a group of chronic non-specific gastrointestinal inflammatory conditions, whose pathogenic factors and pathogenesis may be related to environmental factors, genetic susceptibility, gut microbiota and immune responses. Ferroptosis is a newly found cell death caused by the accumulation of iron-dependent lipid hydroperoxides, which is tightly regulated by a lipid repair system including glutathione (GSH) and glutathione peroxidase 4 (GPx4). Increasing studies have reported the fundamental features of ferroptosis in the injured gastrointestinal tract in IBD patients, including iron deposition, GSH exhaustion, GPx4 inactivation, and lipid peroxidation. Furthermore, regulating the key ferroptosis-related genes may alter the progression, severity, or even morbidity of IBD. We reviewed the basic mechanism of ferroptosis, and the prospect of ferroptosis pathways as therapeutic targets in IBD. In addition, the initiation of ferroptosis for improving IBD by extrinsic (transporter-dependent) or intrinsic (enzyme-regulated) pathway, may be a new direction for clinical treatment of IBD.

Key words: Inflammatory bowel diseases, Ferroptosis, Reactive oxygen species, Lipid peroxidation, Therapy, Reviews

蒲瑜,张吉翔,董卫国. 铁死亡与炎症性肠病的研究进展[J]. 中国全科医学, 2023, 26(29): 3698-3703. DOI: 10.12114/j.issn.1007-9572.2022.0698.
PU Yu,ZHANG Jixiang,DONG Weiguo. Advances in Ferroptosis and Inflammatory Bowel Disease[J]. Chinese General Practice, 2023, 26(29): 3698-3703. DOI: 10.12114/j.issn.1007-9572.2022.0698.

图/表 2

图1 细胞铁死亡通路注：SLC7A11和SLC3A2组成亚基；GCH1=三磷酸鸟苷环水解酶-1，BH4=四氢生物蝶呤，NADP+=烟酰胺腺嘌呤二核苷酸磷酸，NADPH=还原型烟酰胺腺嘌呤二核苷酸磷酸。

Figure 1 Ferroptosis pathway in cells

图2 IBD细胞中铁死亡调控通路注：OTSSP167为Ⅰ型激酶抑制剂；PERK=蛋白激酶R样内质网激酶，ACSL4=长链酰基辅酶ａ合成酶家族成员４，Lip-1=铁死亡抑制剂，Furin=内切蛋白酶，IL-6=白介素6，NF-κB=核因子κB。

Figure 2 Regulatory pathway of ferroptosis in cells in inflammatory bowel disease

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