Nuclear Receptor Nurr1 deactivate HSC through suppressing EMT

Liver fibrosis is characterized by disruption of the hepatic architecture and excessive deposition of an unbalanced extracellular matrix (ECM). Epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of liver fibrosis, with hepatic stellate cells (HSCs) being capable of undergoing EMT. Our previous findings demonstrated that the overexpression of the nuclear receptor Nurr1 inhibited liver fibrosis. However, the underlying mechanism remains unclear. Notably, transfection with a Nurr1-overexpressing plasmid resulted in reduced α-SMA expression and elevated E-CAD expression in HSC-T6 cells, while silencing Nurr1 had the opposite effect. Furthermore, downregulation of Nurr1 led to increased mRNA levels of α-SMA and EMT-related genes, such as Snail, Slug, and Smad3, whereas overexpression of Nurr1 had the opposite effect. Flow cytometry analysis revealed an increase in the number of S phase cells upon modulation of Nurr1 expression; specifically, knockdown of Nurr1 increased the number of G2/M phase cells, while overexpression decreased it. Additionally, chromatin immunoprecipitation experiments indicated that Nurr1 interacts with the promoter region of Smad3. In conclusion, our results suggest that Nurr1 suppresses HSC activation by inhibiting EMT-related genes and modulating the cell cycle by interacting with SMAD3