Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-11-01 Epub Date: 2024-10-29 DOI:10.1038/s44321-024-00160-9
Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen
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Abstract

Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.

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叶黄素通过降解小鼠体内的 Uroc1 蛋白,为 DEHP 解毒并防止肝损伤。
邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种环境污染物,在环境和临床样本中被广泛检测到,对内分泌系统的平衡构成严重威胁。DEHP 在肝脏中的蓄积尤为明显,可导致肝损伤。由于缺乏有效的高通量筛选系统,阻碍了能特异性靶向消除 DEHP 有害影响的药物的发现。在这里,通过开发一种基于Cy5修饰的单链DNA-aptamer方法来靶向DEHP,我们发现了木犀草素这种潜在的药物,它通过促进小鼠原代肝细胞和肝脏中DEHP的排出,在DEHP的解毒方面显示出强大的功效。从机理上讲,木犀草素通过靶向肝脏尿氨酸水解酶1(Uroc1)的Ala270和Val272位点,促进其蛋白质降解。更重要的是,反式尿囊酸(trans-UCA)作为 Uroc1 的底物,通过抑制 ERK1/2 信号级联调节溶酶体的外泌,具有与叶黄素类似的特性。总之,通过调节 UCA/Uroc1 轴,木犀草素可作为一种有效的治疗药物,在肝脏中有效地解毒 DEHP。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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