Nrf2 amplifies oxidative stress via induction of Klf9

Mol Cell. 2014 Mar 20;53(6):916-928. doi: 10.1016/j.molcel.2014.01.033. Epub 2014 Mar 6.


Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Bleomycin
  • Cell Line, Tumor
  • Gene Expression Regulation*
  • Genes, Reporter
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • NIH 3T3 Cells
  • Oxidative Stress*
  • Promoter Regions, Genetic
  • Protein Binding
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • Reactive Oxygen Species
  • Signal Transduction


  • KLF9 protein, human
  • Klf9 protein, mouse
  • Kruppel-Like Transcription Factors
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Bleomycin
  • Luciferases