Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

Trends Pharmacol Sci. 2015 Jan;36(1):6-14. doi: 10.1016/ Epub 2014 Nov 22.


Transcription factors heat shock factor (Hsf)1 and nuclear factor-erythroid 2 p45-related factor (Nrf)2 are critical for adaptation and survival. Each is maintained at low basal levels, but is robustly activated by various stimuli, including cysteine-reactive small molecules (inducers). Although each is regulated by distinct mechanisms, it is emerging that these transcription factors engage in crosstalk by sharing overlapping transcriptional targets, such as heat shock protein (HSP)70, p62, and activating transcription factor (ATF)3, and in certain cases, compensating for each other. Critically, activation of Hsf1 or Nrf2 affects the cellular redox balance by promoting the reduced state. Conversely, deletion of Hsf1 or Nrf2 is associated with oxidative stress and impaired mitochondrial function. Transient activation of Hsf1 and Nrf2 is cytoprotective, but their persistent upregulation may be detrimental, causing cardiomyopathy or accelerating carcinogenesis, and should be considered when designing strategies for disease prevention and treatment.

Keywords: Kelch-like ECH associated protein 1 (Keap1); cysteine reactivity; glutathione; heat shock; mitochondrial function; redox.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoprotection*
  • DNA-Binding Proteins / metabolism*
  • Heat Shock Transcription Factors
  • Humans
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidation-Reduction
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • NF-E2-Related Factor 2
  • Transcription Factors