Iron chelation by deferasirox confers protection against concanavalin A-induced liver fibrosis: A mechanistic approach

• Published in: Toxicology and applied pharmacology Vol. 382; p. 114748
• Main Authors: Adel, Nada, Mantawy, Eman M., El-Sherbiny, Doaa A., El-Demerdash, Ebtehal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2019
• Subjects: Animals; Concanavalin A; Concanavalin A - toxicity; Deferasirox; Deferasirox - therapeutic use; Hepcidin; Iron Chelating Agents - therapeutic use; Iron overload; Iron Overload - chemically induced; Iron Overload - metabolism; Iron Overload - prevention & control; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - prevention & control; Liver fibrosis; Male; Rats; Rats, Sprague-Dawley; Iron overload; AST; Con A; ALT; Liver fibrosis; MDA; Concanavalin A; ECM; NOX-4; Deferasirox; NF-κB; α-SMA; TIBC; IFN-γ; P-CREB; TNF-α; TSAT; CAT; DFX; CHOP; iNOS; HCV; HSCs; Hepcidin
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114748

Hepatic iron overload is one of the causative factors for chronic liver injury and fibrosis. The present study aimed to investigate the potential antifibrotic effect of the iron chelator; deferasirox (DFX) in experimentally-induced liver fibrosis in rats. Male Sprague-Dawley rats were administered concanavalin A (Con A) and/or DFX for 6 consecutive weeks. Con A injection induced significant hepatotoxicity as was evident by the elevated transaminases activity, and decreased albumin level. Also, it disturbed the iron homeostasis through increasing C/EBP homologous protein (CHOP), decreasing phosphorylated cAMP responsive element binding protein(P-CREB) and hepcidin levels leading to significant serum and hepatic iron overload. In addition, it induced an imbalance in the oxidative status of the liver via upregulating NADPH oxidase 4 (NOX4), together with a marked decrease in anti-oxidant enzymes' activities. As a consequence, upregulation of nuclear factor-kappa b (NF-κB) and the downstream inflammatory mediators was observed. Those events all together precipitated in initiation of liver fibrosis as confirmed by the elevation of alpha-smooth muscle actin (α-SMA) and liver collagen content. Co-treatment with DFX protected against experimentally-induced liver fibrosis in rats via its iron chelating, anti-oxidant, and anti-inflammatory properties. These findings imply that DFX can attenuate the progression of liver fibrosis. [Display omitted] •DFX attenuated Con A-induced hepatic damage and histopathological injury.•Hepatic fibrogenesis and collagen deposition were alleviated by DFX co-treatment.•As an antioxidant, DFX reduced NOX-4 expression and preserved the antioxidant enzymes.•DFX diminished the Con A-induced elevation of NF-κB, TNF-α, IFN-γ, and iNOS.•DFX restored CHOP, P-CREB, and hepcidin levels, thus preventing hepatic iron overload.