More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

Biomolecules. 2021 Mar 31;11(4):523. doi: 10.3390/biom11040523.


Cells encounter a myriad of endogenous and exogenous stresses that could perturb cellular physiological processes. Therefore, cells are equipped with several adaptive and stress-response machinery to overcome and survive these insults. One such machinery is the heat shock response (HSR) program that is governed by the heat shock factors (HSFs) family in response towards elevated temperature, free radicals, oxidants, and heavy metals. HSF4 is a member of this HSFs family that could exist in two predominant isoforms, either the transcriptional repressor HSFa or transcriptional activator HSF4b. HSF4 is constitutively active due to the lack of oligomerization negative regulator domain. HSF4 has been demonstrated to play roles in several physiological processes and not only limited to regulating the classical heat shock- or stress-responsive transcriptional programs. In this review, we will revisit and delineate the recent updates on HSF4 molecular properties. We also comprehensively discuss the roles of HSF4 in health and diseases, particularly in lens cell development, cataract formation, and cancer pathogenesis. Finally, we will posit the potential direction of HSF4 future research that could enhance our knowledge on HSF4 molecular networks as well as physiological and pathophysiological functions.

Keywords: cancer; cataract; cells development; cellular stress; heat shock factors; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cataract / metabolism
  • Cataract / pathology*
  • Cell Differentiation
  • Heat Shock Transcription Factors / classification
  • Heat Shock Transcription Factors / genetics
  • Heat Shock Transcription Factors / metabolism*
  • Humans
  • Lens, Crystalline / cytology
  • Lens, Crystalline / metabolism
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Phylogeny
  • Protein Isoforms / classification
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary


  • HSF4 protein, human
  • Heat Shock Transcription Factors
  • Protein Isoforms