Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism

Our investigation demonstrated that UA-NSps exhibited high drug-loading capacity, spherical morphology, and improved dissolution and oral bioavailability. In the ANIT model, UA-NSps effectively restored liver function, as evidenced by histopathological and biochemical improvements. Mechanistically, UA-NSps enhanced Nrf2 nuclear translocation, upregulated Nrf2 and HO-1, reduced pro-inflammatory cytokines, and ameliorated mitochondrial damage. Moreover, UA-NSps alleviated the bile acid metabolism disorders by upregulating the transcriptional activity of UGT2B1, BSEP, and MRP2, as well as the protein expression of nuclear receptors and metabolic enzymes PXR,CYP3A4, and UGT1A1. Our study presents a novel drug-drug nanocrystal strategy that enhances the therapeutic efficacy against CLI by inhibiting oxidative stress and regulating bile acid metabolism.