Quercetin ameliorates liver fibrosis in Wilson disease and EMT involving suppression of the Hedgehog signaling pathway

Liver fibrosis is a fundamental pathological alteration observed in individuals with Wilson disease. Quercetin (Que) has shown potential in inhibiting fibrosis in various diseases. However, the precise mechanism by which Que alleviates liver fibrosis in Wilson disease remains unclear. The present study aimed to investigate the potential role of Que in liver fibrosis of Wilson disease using male Toxic Milk (TX) mice and Cu2+-induced hepatoblastoma cells (HepG2 cells). In TX mice, Analyses using Histopathology , Immunohistochemical staining, Enzyme-linked immunosorbent assay (ELISA), and Western blot, revealed that Que treatment facilitated the efflux of Cu2+ from the liver, improvement of liver function indicators and pathological damage of liver tissue, and significantly inhibited Hedghog (Hh) signaling pathway, leading to significant downregulation of key proteins and genes involved in this pathway, including Gli1, Ptch1, Smo, and Shh. Moreover, Que can reverse epithelial-mesenchymal transition (EMT), and we have also investigated key proteins and genes of EMT and the specific transcription factors controlling E-cadherin expression at the transcriptional level (Slug, Snail, ZEB-1, and Twist) and found that Que can regulatory their expression levels. In Cu2+-induced HepG2 cells, we using Hh Signaling pathway Inhibitor: GDC-0449, found blocking Hh Signaling pathway can reverse the EMT and consistent with in vivo results. Therefore, Que may have the potential to ameliorate liver fibrosis in Wilson disease and EMT by suppressing the Hh signaling pathway.