SIRT3, NF-κB/TNF-α and PI3K/Akt Pathways Mediate the Hepatoprotective Activity of Gossypin Against Concanavalin A-Induced Hepatic Fibrosis

Chronic liver damage usually results in a pathological state of excessive deposition of extracellular matrix that is known as liver fibrosis. This study was designed to examine the potential preventive effect of the pentahydroxyglucosyl flavone, gossypin (GPN), against concanavalin A (Con A)-induced liver fibrosis in BALB/c albino mice. Methods: Liver fibrosis was induced by intravenous (IV) injection of Con A (10 mg/kg) once weekly for 4 weeks. GPN (10 and 20 mg/kg) was administered orally three times weekly for 4 weeks. At the end of the experiment, serum and liver tissue were obtained and used for different biochemical, histological, histochemical and molecular assessments. GPN (10 and 20 mg/kg) considerably ameliorated liver fibrosis induced by Con A. A marked decrease in serum levels of ALT, AST and LDH was observed upon GPN treatment, confirmed by histopathological analysis by H&E. GPN markedly reduced collagen deposition as confirmed by MT staining, reduced hepatic levels of Col-1 and TGF-β as well as inhibited α-SMA immunostaining. The hepatic oxidative stress biomarker, MDA, was markedly reduced, whereas hepatic antioxidant defense, TAC, was significantly enhanced. Furthermore, GPN effectively enhanced gene and protein expression of SIRT3. GPN downregulated hepatic proinflammatory biomarkers, NF-κB and TNF-α. Additionally, GPN caused a noticeable increase in the hepatic levels and expression of PI3K and Akt. GPN effectively attenuated Con A-induced liver fibrosis via reducing liver damage and collagen deposition majorly by lessening inflammation, oxidative stress and fibrosis. GPN modulated SIRT3, NF-κB/TNF-α and PI3K/Akt pathways.