Taxifolin ameliorates iron overload-induced hepatocellular injury: Modulating PI3K/AKT and p38 MAPK signaling, inflammatory response, and hepatocellular regeneration

Although physiological levels of iron are essential for numerous biological processes, excess iron causes critical tissue injury. Under iron overload conditions, non-chelated iron generates Reactive Oxygen Species that mediate iron-induced tissue injury with subsequent induction of Apoptosis, necrosis, and inflammatory responses. Because liver is a central player in iron metabolism and storage, it is vulnerable to iron-induced tissue injury. Taxifolin is naturally occurring compound that has shown potent antioxidant and potential iron chelation competency. The aim of the current study was to investigate the potential protective effects of taxifolin against iron-induced hepatocellular injury and to elucidate the underlining mechanisms using rats as a mammalian model. The results of the current work indicated that taxifolin inhibited iron-induced Apoptosis and enhanced hepatocellular survival as demonstrated by decreased activity of Caspase-3 and activation of the pro-survival signaling PI3K/Akt, respectively. Western blotting analysis revealed that taxifolin enhanced liver regeneration as indicated by increased PCNA protein abundance. Taxifolin mitigated the iron-induced histopathological aberration and reduced serum activity of liver enzymes (ALT and AST), highlighting enhanced liver cell integrity. Mechanistically, taxifolin modulated the redox-sensitive MAPK signaling (p38/c-Fos) and improved redox status of the liver tissues as indicated by decreased lipid peroxidation and protein oxidation along with enhanced total antioxidant capacity. Interestingly, it decreased liver iron content and down-regulated the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Collectively, these data highlight, for the first time, the ameliorating effects of taxifolin against iron overload-induced hepatocellular injury that is potentially mediated through anti-inflammatory, antioxidant, and potential iron chelation activities.