Umbelliferone Ameliorates CCl4-Induced Liver Fibrosis in Rats by Upregulating PPARγ and Attenuating Oxidative Stress, Inflammation, and TGF-β1/Smad3 Signaling

Abstract

Umbelliferone (UMB) is a natural coumarin that has diverse biological activities. However, its potential to protect against liver fibrosis has not been reported yet. This study aimed to investigate the protective effect of UMB against carbon tetrachloride (CCl₄)-induced liver fibrosis in rats. Rats received CCl₄ and UMB for 8 weeks and samples were collected for analyses. CCl₄ induced a significant increase in serum levels of liver function markers and pro-inflammatory cytokines. Treatment with UMB significantly ameliorated liver function markers and pro-inflammatory cytokines and prevented CCl₄-induced histological alterations. CCl₄ promoted significant upregulation of α-smooth muscle actin (SMA), collagen I, collagen III, NF-κB p65, TGF-β1, and p-Smad3. Masson's trichrome staining revealed a significant fibrogenesis in CCl₄-induced rats. Treatment with UMB suppressed TGF-β1/Smad3 signaling and downregulated α-SMA, collagen I, collagen III, and NF-κB p65. In addition, UMB diminished malondialdehyde and nitric oxide levels, boosted reduced glutathione and antioxidant enzymes, and upregulated the expression of PPARγ. In conclusion, our results demonstrated that UMB prevented CCl₄-induced liver fibrosis by attenuating oxidative stress, inflammation, and TGF-β1/Smad3 signaling, and upregulating PPARγ. Therefore, UMB may be a promising candidate for preventing hepatic fibrogenesis, given that further research is needed to delineate the exact molecular mechanisms underlying its antifibrotic efficacy.

Keywords: 7-hydroxycoumarin; PPARγ; TGF-β1; fibrosis; inflammation; oxidative stress.