Icaritin Attenuates HSC Activation by Down-regulating the HIF-1α and TGF-β/Smad Signaling Pathways to Ameliorate Liver Fibrosis

Introduction: Icaritin is a bioactive flavonol isolated from the Chinese medicinal herb Epimedium. The comprehensive understanding of antifibrotic effects and associated molecular mechanisms of icaritin remains incomplete. This study aims to explore the protective effects of icaritin against liver fibrosis and to further elucidate the mechanisms involved. Methods: Human hepatic stellate LX-2 cells stimulated with TGF-β1 and a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model were employed. in vitro assays were carried out to evaluate collagen type I (COl I) and α-smooth muscle actin (α-SMA) expression, while in vivo studies assessed fibrosis alleviation. Molecular mechanisms were explored via analysis of TGF-β1, phosphorylated Smad2/3, and HIF-1α protein levels using Western blotting. Results: Icaritin suppressed TGF-β1-induced COl I and α-SMA expression in LX-2 cells and ameliorated liver fibrosis in CCl4-treated mice. Mechanistically, it significantly reduced TGF-β1 levels, inhibited Smad2/3 phosphorylation, and downregulated HIF-1α protein expression in LX-2 cells. Conclusion: Icaritin attenuated experimental liver fibrosis through the inhibition of the TGF-β/Smad and HIF-1α signaling pathways, highlighting its therapeutic potential for fibrotic liver diseases.