{"title":"Enterolactone mitigates atherosclerosis by facilitating resolution of ferroptosis-associated intimal inflammation via the Keap1/Nrf2/GPX4 pathway.","authors":"Shuhui Chai, Yihang Zhang, Yi Guo, Danli Cao, Jiaxing Wang, Yu Yan, Yuxue Shi, Zhiyi Yuan, Xiaoyu Wang, Tingting Tong, Ziyi Zhen, Yanhao Huo, Kaiwen Zhang, Fenglin Wang, Gui-Rong Liu, Weiheng Li, Xiaohui Xu, Tao Ban, Shu-Lin Liu, Huidi Liu","doi":"10.1016/j.phymed.2026.158178","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear.</p><p><strong>Purpose: </strong>To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism.</p><p><strong>Methods: </strong>We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H<sub>2</sub>O<sub>2</sub> was used to induce HUVEC injury and ferroptosis to mimic endothelial cell dysfunction in atherosclerosis, and the inhibitory effect of ENL on HUVEC ferroptosis was appraised by monitoring ferroptosis indexes and levels of iron-related proteins.</p><p><strong>Results: </strong>In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL.</p><p><strong>Conclusion: </strong>Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"155 ","pages":"158178"},"PeriodicalIF":8.3000,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.phymed.2026.158178","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/4/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear.
Purpose: To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism.
Methods: We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H2O2 was used to induce HUVEC injury and ferroptosis to mimic endothelial cell dysfunction in atherosclerosis, and the inhibitory effect of ENL on HUVEC ferroptosis was appraised by monitoring ferroptosis indexes and levels of iron-related proteins.
Results: In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL.
Conclusion: Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway.
期刊介绍：
Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
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