Mechanism of endoplasmic reticulum stress-induced endothelial cell ferroptosis in trichloroethylene-induced mouse kidney injury.

IF 3.3 4区医学 Q4 TOXICOLOGY

Toxicological Research Pub Date : 2025-07-26 eCollection Date: 2025-11-01 DOI:10.1007/s43188-025-00307-x

Meng Huang, Jiaxiang Zhang, Rui Li, Jian Chen, Qixing Zhu, Haibo Xie

{"title":"Mechanism of endoplasmic reticulum stress-induced endothelial cell ferroptosis in trichloroethylene-induced mouse kidney injury.","authors":"Meng Huang, Jiaxiang Zhang, Rui Li, Jian Chen, Qixing Zhu, Haibo Xie","doi":"10.1007/s43188-025-00307-x","DOIUrl":null,"url":null,"abstract":"Trichloroethylene (TCE) is widely employed as a cleaning agent in industrial settings. Occupational exposure to TCE can lead to occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Our previous research has identified damage to renal vascular endothelial cells (ECs) in both OMDT patients and TCE-sensitized mice; however, the underlying mechanisms remain insufficiently understood. Methods: This study aims to elucidate the role of endoplasmic reticulum stress (ERS)-induced ECs ferroptosis in TCE-induced renal injury by developing a TCE-sensitization mouse model. Our findings indicate that ferroptosis in renal ECs is associated with TCE-induced kidney damage, and the ferroptosis inhibitor Fer-1 can mitigate this injury. Notably, ERS can modulate TCE-induced ECs ferroptosis. The PERK inhibitor GSK2606414 can suppress ferroptosis via the Nrf2/HO-1 signaling pathway and reduce trichloroethylene-induced renal injury. In conclusion, TCE sensitization activates ERS through the PERK/eIF2α/ATF4 pathway, with PERK subsequently mediating ferroptosis of renal vascular endothelial cells via the Nrf2/HO-1 signaling pathway, thereby contributing to TCE-related immune kidney injury.Graphical abstract: ","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"41 6","pages":"623-634"},"PeriodicalIF":3.3000,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12569308/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicological Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s43188-025-00307-x","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/11/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"TOXICOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Trichloroethylene (TCE) is widely employed as a cleaning agent in industrial settings. Occupational exposure to TCE can lead to occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Our previous research has identified damage to renal vascular endothelial cells (ECs) in both OMDT patients and TCE-sensitized mice; however, the underlying mechanisms remain insufficiently understood. Methods: This study aims to elucidate the role of endoplasmic reticulum stress (ERS)-induced ECs ferroptosis in TCE-induced renal injury by developing a TCE-sensitization mouse model. Our findings indicate that ferroptosis in renal ECs is associated with TCE-induced kidney damage, and the ferroptosis inhibitor Fer-1 can mitigate this injury. Notably, ERS can modulate TCE-induced ECs ferroptosis. The PERK inhibitor GSK2606414 can suppress ferroptosis via the Nrf2/HO-1 signaling pathway and reduce trichloroethylene-induced renal injury. In conclusion, TCE sensitization activates ERS through the PERK/eIF2α/ATF4 pathway, with PERK subsequently mediating ferroptosis of renal vascular endothelial cells via the Nrf2/HO-1 signaling pathway, thereby contributing to TCE-related immune kidney injury.

Graphical abstract:

查看原文本刊更多论文

内质网应激诱导三氯乙烯致小鼠肾损伤内皮细胞铁下垂的机制。

三氯乙烯（TCE）被广泛用作工业环境中的清洗剂。职业性接触三氯乙烯可导致职业性药物样三氯乙烯皮炎（OMDT）。我们之前的研究已经确定了OMDT患者和tce致敏小鼠的肾血管内皮细胞（ECs）损伤；然而，潜在的机制仍然没有得到充分的了解。方法：通过建立tce致敏小鼠模型，探讨内质网应激（ERS）诱导的ECs铁下垂在tce致敏小鼠肾损伤中的作用。我们的研究结果表明，肾内皮细胞的铁下垂与tce引起的肾损伤有关，铁下垂抑制剂Fer-1可以减轻这种损伤。值得注意的是，ERS可以调节tce诱导的ECs铁下垂。PERK抑制剂GSK2606414可通过Nrf2/HO-1信号通路抑制铁下垂，减轻三氯乙烯所致肾损伤。综上所述，TCE致敏通过PERK/eIF2α/ATF4通路激活ERS， PERK随后通过Nrf2/HO-1信号通路介导肾血管内皮细胞铁凋亡，从而导致TCE相关的免疫肾损伤。图形化的简介:

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Toxicological Research TOXICOLOGY-

CiteScore

4.20

自引率

4.30%

发文量

期刊介绍： Toxicological Research is the official journal of the Korean Society of Toxicology. The journal covers all areas of Toxicological Research of chemicals, drugs and environmental agents affecting human and animals, which in turn impact public health. The journal’s mission is to disseminate scientific and technical information on diverse areas of toxicological research. Contributions by toxicologists, molecular biologists, geneticists, biochemists, pharmacologists, clinical researchers and epidemiologists with a global view on public health through toxicological research are welcome. Emphasis will be given to articles providing an understanding of the toxicological mechanisms affecting animal, human and public health. In the case of research articles using natural extracts, detailed information with respect to the origin, extraction method, chemical profiles, and characterization of standard compounds to ensure the reproducible pharmacological activity should be provided.