The dark side of NRF2 in arsenic carcinogenesis

Matthew Dodson, Jinjing Chen, Aryatara Shakya, Annadurai Anandhan, Donna D. Zhang

Research output: Chapter in Book/Report/Conference proceedingChapter


Arsenic is an environmental toxicant that significantly enhances the risk of developing disease, including several cancers. While the epidemiological evidence supporting increased cancer risk due to chronic arsenic exposure is strong, therapies tailored to treat exposed populations are lacking. This can be accredited in large part to the chronic nature and pleiotropic pathological effects associated with prolonged arsenic exposure. Despite this fact, several putative mediators of arsenic promotion of cancer have been identified. Among these, the critical transcription factor NRF2 has been shown to be a key mediator of arsenic's pro-carcinogenic effects. Importantly, the dependence of arsenic-transformed cancer cells on NRF2 upregulation exposes a targetable liability that could be utilized to treat arsenic-promoted cancers. In this chapter, we briefly introduce the “light” vs “dark” side of the NRF2 pathway. We then give a brief overview of arsenic metabolism, and discuss the epidemiological and experimental evidence that support arsenic promotion of different cancers, with a specific emphasis on mechanisms mediated by chronic, non-canonical activation of NRF2 (i.e., the “dark” side). Finally, we briefly highlight how the non-canonical NRF2 pathway plays a role in other arsenic-promoted diseases, as well as research directions that warrant further investigation.

Original languageEnglish (US)
Title of host publicationEnvironmental Carcinogenesis
EditorsMax Costa
PublisherAcademic Press Inc.
Number of pages23
ISBN (Print)9780323997751
StatePublished - Jan 2023

Publication series

NameAdvances in Pharmacology
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925


  • Arsenic
  • Cancer
  • Canonical vs non-canonical NRF2
  • Carcinogenesis
  • Dark side of NRF2

ASJC Scopus subject areas

  • Pharmacology


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