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

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.