Dehydrozingerone ameliorates thioacetamide-induced liver fibrosis via inhibition of hepatic stellate cells activation through modulation of the MAPK pathway

Abstract

Hepatic fibrosis is a progressive consequence of injury to the liver cells. Liver fibrosis causes hepatic dysfunction and also plays a key role in the pathogenesis of other chronic ailments. Dehydrozingerone (DHZ) is a half-structural analogue of curcumin and is known to have several therapeutic benefits. However, the impact of DHZ on liver fibrosis was not investigated. The current investigation attempted to determine the anti-fibrotic effect of DHZ against thioacetamide-induced liver fibrosis in rats and TGF-β-induced differentiation in human HSC-LX2 cells and to uncover the possible mechanisms. In in-vivo, DHZ significantly reduced the TAA-induced liver index and ameliorated the liver functional parameters. TAA elevated the fibrotic marker's expression in TAA control, on the other hand, DHZ treatment significantly mitigated the same in mRNA and protein levels. Additionally, these findings were supported by histological investigations and immunohistochemistry studies of the fibrotic marker's expressions. DHZ treatment effectively reduced oxidative stress by increasing catalase activity and decreased the expression of inflammatory markers (myeloperoxidase and neutrophil-elastase) in liver tissues. Additionally, collagen staining and histological findings confirmed that DHZ administration significantly reduced TAA induced pathological deformities and elevated collagen levels. In-vitro results showed that TGF-β-induced differentiation was suppressed by DHZ treatment in a dose-dependent manner. Mechanistic approaches in HSC-LX2 and liver tissues revealed that DHZ treatment mitigated fibrosis by modulating the MAPK-pathway. Overall, these results show that DHZ exhibited anti-fibrotic action by reducing fibrotic markers and their activities through regulation of the MAPK-pathway, suggesting that DHZ may be a promising therapeutic molecule for liver fibrosis.