Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis

Antioxid Redox Signal. 2018 Jan 1;28(1):1-14. doi: 10.1089/ars.2017.7051. Epub 2017 Sep 6.


Aims: Iron overload (IO) is a life-threatening complication of chronic hemolytic disorders such as β-thalassemia. IO results in severe cellular oxidative damage, leading to organ failure. Peroxiredoxin-2 (Prx2), a typical 2-cysteine-(Cys)-peroxiredoxin, is an important component of the cytoprotective system, but its response to IO is still to be fully defined.

Results: We studied the effects of IO on Prx2-knockout mice (Prx2-/-). The absence of Prx2 enhanced toxicity due to IO on erythropoiesis. We found that IO failed to induce the typical hepcidin (Hamp) upregulation in Prx2-/- mice due to its failure to activate the signal transducer and activator of transcription-3 (STAT3) with intact Jak2 signaling. In Prx2-/- mice, the loss of Hamp response was also observed after administration of a single dose of oral iron. When lipopolysaccharide (LPS) was used to explore IL6-STAT3 activation in Prx2-/- mice, STAT3 activation and Hamp upregulation were once again defective. Treatment with PEP-fusion-recombinant-Prx2 (PEP Prx2) significantly increased STAT3 activation with upregulation of Hamp expression in both IO- and LPS-exposed Prx2-/- mice. We also confirmed the beneficial effects of PEP Prx2 on Hamp expression through STAT3 activation in β-thalassemic mice.

Innovation: We propose that Prx2 plays a key role in responding to cytotoxicity of IO, directly targeting STAT3-transcriptional factor in a Jak2-independent fashion and regulating Hamp in response to canonical stimuli.

Conclusion: Collectively, our data highlight a novel role of Prx2 in iron homeostasis. Prx2 is a key cytoprotector against IO that is induced either by iron supplementation or due to chronic hemolysis as in β-thalassemia. Prx2 is required to support STAT3 transcriptional activity and regulation of Hamp expression. Antioxid. Redox Signal. 28, 1-14.

Keywords: hepcidin; iron overload; peroxiredoxin-2.

MeSH terms

  • Anemia / drug therapy
  • Anemia / etiology
  • Anemia / metabolism
  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cytoprotection / genetics
  • Disease Models, Animal
  • Erythropoiesis*
  • Gene Expression Regulation / drug effects
  • Hepcidins / genetics
  • Hepcidins / metabolism
  • Homeostasis*
  • Iron / metabolism*
  • Iron Overload / etiology
  • Iron Overload / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Oxidative Stress
  • Peroxiredoxins / genetics*
  • Peroxiredoxins / metabolism*
  • Peroxiredoxins / pharmacology
  • Recombinant Proteins
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Hepcidins
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Transcription Factors
  • Iron
  • Peroxiredoxins