DDIT4通过铁死亡的代谢调控在幽门螺杆菌诱导的胃化生中的保护作用
The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis.
作者信息
Wang Huan, Xu Xinbo, Ouyang Yaobin, Fei Xiao, He Cong, Yang Xianhe, Ren Yuping, Zhou Yanan, Chen Sihai, Hu Yi, Liu Jianping, Ge Zhongming, Wu William Ka Kei, Lu Nonghua, Xie Chuan, Wu Xidong, Zhu Yin, Li Nianshuang
机构信息
Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
出版信息
Cell Mol Gastroenterol Hepatol. 2025;19(5):101448. doi: 10.1016/j.jcmgh.2024.101448. Epub 2024 Dec 27.
BACKGROUND & AIMS: Helicobacter pylori (H pylori) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of H pylori infection.
METHODS
Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on Ddit4 and Ddit4 mice infected with H pylori strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins.
RESULTS
DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to H pylori infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post H pylori infection. Notably, H pylori infection led to more severe gastric metaplasia lesion in Ddit4-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected Ddit4-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted H pylori-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted H pylori-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis.
CONCLUSIONS
Our results indicate that DDIT4 serves as a protective factor against H pylori-induced gastric metaplasia by metabolic resistance to ferroptosis.
背景与目的
幽门螺杆菌（H pylori）感染是导致胃萎缩、化生及癌症发生的重要因素。在此，我们研究了应激反应基因DDIT4在幽门螺杆菌感染发病机制中的作用。
方法
采用细胞系、转基因小鼠和人体组织样本。对感染幽门螺杆菌菌株PMSS1的Ddit4和Ddit4小鼠进行蛋白质组学分析。给C57BL/6小鼠注射他莫昔芬以诱导胃化生。对胃组织进行组织病理学特征、活性氧、铁、脂质过氧化、DDIT4表达及铁死亡相关蛋白的分析。
结果
胃上皮细胞中，幽门螺杆菌感染后6小时DDIT4表达上调，但24小时时显著下降。幽门螺杆菌感染4个月后，INS-GAS小鼠胃中的DDIT4下调。值得注意的是，幽门螺杆菌感染在Ddit4基因敲除小鼠中导致更严重的胃化生病变。蛋白质组学分析显示，与感染的野生型小鼠相比，感染的Ddit4缺陷小鼠胃组织中的铁死亡增加。机制上，DDIT4基因敲除通过脂质过氧化物和ROS水平的积累以及GPX4、ALOX15和HMOX1等蛋白质的改变促进幽门螺杆菌诱导的铁死亡。DDIT4的过表达通过调节铁死亡抵消了幽门螺杆菌诱导的干细胞标志物CD44V9。同样，在另一种用他莫昔芬治疗的胃化生小鼠模型以及人体胃化生组织中，我们观察到DDIT4的缺失和铁死亡的诱导。
结论
我们的结果表明，DDIT4通过对铁死亡的代谢抗性，作为对抗幽门螺杆菌诱导的胃化生的保护因子。
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