The role of nuclear factor erythroid 2-related factor 2 (NRF2) in arsenic toxicity

• Published in: Journal of environmental sciences (China) 2025-04, Vol.150, p.632-644
• Main Authors: El-Mahrouk, Sara R., El-Ghiaty, Mahmoud A., El-Kadi, Ayman O.S.
• Format: Article
• Language: English
• Subjects: Antioxidants - metabolism; Arsenic; Arsenic - toxicity; HMOX1; Humans; KEAP1; NF-E2-Related Factor 2 - metabolism; NQO1; NRF2; Oxidative stress; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism
• ISSN: 1001-0742
• DOI: 10.1016/j.jes.2024.02.027

•NRF2 exhibits a dual function in cancer, serving both as a protective shield against oxidative stress and potentially promoting the survival of cancer cells.•Arsenic-induced cytotoxicity is attributed to oxidative stress, primarily through ROS generation, alongside elevated intracellular metal accumulation.•Arsenicals differentially modulates NRF2 transcription factor and its downstream targets.•Inorganic arsenic induces both NRF2 nuclear import and BACH1 export, whereas organic arsenic specifically triggers NRF2 translocation. Arsenic, a naturally occurring toxic element, manifests in various chemical forms and is widespread in the environment. Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases. The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress, characterized by an unsettling imbalance between oxidants and antioxidants, accompanied by the rampant generation of reactive oxygen species and free radicals. In response to this oxidative turmoil, cells deploy their defense mechanisms, prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic. When oxidative stress activates NRF2, it orchestrates a symphony of downstream antioxidant genes, leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase, heme oxygenase-1, and NAD(P)H: quinone oxidoreductase 1. This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets, shedding light on their roles in defending against arsenic exposure toxic effects. It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure. [Display omitted]