Modulating NF‐κB, MAPK, and PI3K/AKT signaling by ergothioneine attenuates iron overload‐induced hepatocellular injury in rats

Abstract The liver is highly susceptible to iron overload‐evoked oxidative injury. Ergothioneine is a thio‐histidine amino acid that has exhibited strong antioxidant and metal chelating activities. This study aimed at exploring the potential modulating effects of ergothioneine on iron‐triggered liver injury. The results showed that ergothioneine inhibited iron‐evoked inflammation and apoptosis as demonstrated by a significant reduction in tumor necrosis factor‐α and interleukin‐6 levels and in caspase‐3 activity. Ergothioneine significantly improved liver cell survival as indicated by modulating phosphatidylinositol 3‑kinase/protein kinase B signaling. Consistent with reduced necrotic cell death, ergothioneine diminished the iron‐evoked histopathological changes and decreased serum activity of the liver enzymes. Mechanistically, ergothioneine reduced nuclear translocation of nuclear factor kappa B p65 and modulated p38 mitogen‐activated protein kinase/c‐Fos signaling. In addition, it enhanced the liver tissue antioxidant potential and curbed hepatic iron load. Together, these results point out the modulatory effects of ergothioneine on iron‐evoked liver cell injury that are possibly mediated via anti‐inflammatory, antioxidant, and possible iron chelation capabilities.