HIFs and NRF2, adaptive response systems to variable oxygen availability

[Left] In hypoxic conditions, HIFs stabilize, translocate into the nucleus, and bind to the HRE, thereby inducing the expression of their target genes. In the presence of oxygen, HIFs are continuously degraded by the canonical PHD/pVHL-mediated pathway. The regulatory mechanism of FIH-1 also contributes to the inhibition of HIF activity. [Right] NRF2 maintains cellular redox homeostasis in response to oxidative stress, which can be induced by an excess oxygen environment. ROS/electrophiles and nonelectrophiles, such as p62, can inhibit NRF2-KEAP1 interactions to activate NRF2 target gene expression. This inhibition occurs through the KEAP1 Cys modification and competition with KEAP1 for binding to NRF2. Additionally, as a KEAP1-independent regulatory pathway, NRF2 phosphorylation by GSK-3β leads to β-TrCP-mediated proteasomal degradation of NRF2

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Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer (2024) Taegeun Bae, et al. Exp Mol Med. 2024 Mar;56(3). Figure: F1. All organisms Caenorhabditis elegans Homo sapiens

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