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.

中文翻译：

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木犀草素通过降解小鼠的 Uroc1 蛋白来解毒 DEHP 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，已在环境和临床样本中广泛检测到，对内分泌系统的稳态构成严重威胁。DEHP 的积累在肝脏中明显明显，可导致肝损伤。缺乏有效的高通量筛选系统阻碍了可以专门针对和消除 DEHP 有害影响的此类药物的发现。在这里，通过开发一种靶向 DEHP 的基于 Cy5 修饰的单链 DNA 适配体的方法，我们已经确定木犀草素是一种潜在的药物，它通过促进小鼠原代肝细胞和肝脏中 DEHP 的排出，在解毒 DEHP 方面表现出强大的功效。从机制上讲，木犀草素通过靶向肝尿酸水合酶 1 （Uroc1） 的 Ala270 和 Val272 位点来增强蛋白质降解。更重要的是，反式尿酸 （trans-UCA） 作为 Uroc1 的底物，通过抑制 ERK1/2 信号级联调节溶酶体胞吐作用，具有类似于木犀草素的特性。总之，木犀草素是一种有效的治疗剂，通过调节 UCA/Uroc1 轴有效地解毒肝脏中的 DEHP。