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

J Biochem Mol Toxicol. 2021 May;35(5):e22729. doi: 10.1002/jbt.22729. Epub 2021 Feb 13.


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.

Keywords: NF-κB; TNF-α; ergothioneine; hepatocellular injury; iron overload.

MeSH terms

  • Animals
  • Ergothioneine / pharmacology*
  • Iron Overload* / drug therapy
  • Iron Overload* / metabolism
  • Iron Overload* / pathology
  • Liver* / injuries
  • Liver* / metabolism
  • Liver* / pathology
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Wistar
  • Transcription Factor RelA / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Proto-Oncogene Proteins c-fos
  • Rela protein, rat
  • Transcription Factor RelA
  • Ergothioneine
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases