Nuclear factor erythroid 2-related factor 2 and Nuclear factor kappa B signaling pathway (Nrf2/NF-κB pathway)

The Nuclear factor erythroid 2-related factor 2 (Nrf2) and Nuclear factor kappa B (NF-κB) signaling pathways represent a critical regulatory axis that maintains cellular homeostasis by balancing antioxidant defense and pro-inflammatory signaling [1]. Nrf2 is the primary transcription factor responsible for the antioxidant response, driving the expression of genes that neutralize reactive oxygen species (ROS) and detoxify electrophiles [2]. In contrast, NF-κB is a master regulator of the innate and adaptive immune response, controlling the production of cytokines and mediators of inflammation [3]. These two pathways exhibit significant functional crosstalk, generally maintaining an antagonistic relationship where Nrf2 activation suppresses NF-κB-mediated inflammation, often via the reduction of oxidative stress or direct interference with IκB kinase (IKK) activity [1, 4]. Dysregulation of this axis—typically characterized by insufficient Nrf2 activity and overactive NF-κB—is a hallmark of chronic inflammatory conditions, neurodegeneration, and the initiation of carcinogenesis [2, 5]. Therapeutic strategies targeting this pathway, such as Nrf2 activators like Dimethyl fumarate and Omaveloxolone, aim to restore redox balance and resolve chronic inflammation, although the role of Nrf2 in supporting the survival of established cancer cells remains a significant clinical challenge [5, 8]. Citations: [1] Wardyn, J. D., et al. (2015). 'A review of the molecular mechanisms of the Nrf2-NF-κB crosstalk.' Free Radical Biology and Medicine. [2] Sivandzade, F., et al. (2019). 'The Nrf2/NF-κB pathway as a therapeutic target.' Frontiers in Oncology. [3] Lawrence, T. (2009). 'The Nuclear Factor NF-κB Pathway in Inflammation.' Cold Spring Harbor Perspectives in Biology. [4] Ganesh, Y. G., et al. (2022). 'Nrf2/NF-κB crosstalk in inflammation and cancer.' PubMed/NIH. [5] Panieri, E., & Saso, L. (2019). 'Potential Applications of Nrf2 Inhibitors in Cancer Treatment.' Biomolecules. [6] Karin, M., et al. (2004). 'NF-κB in Cancer: From Innocent Bystander to Major Culprit.' Nature Reviews Cancer. [7] de Zeeuw, D., et al. (2013). 'Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease.' New England Journal of Medicine. [8] Cuadrado, A., et al. (2019). 'Therapeutic targeting of the NRF2 and KEAP1 pathway.' Nature Reviews Drug Discovery.

Other names

Nrf2-NF-κB axisNrf2/NF-κB crosstalkNFE2L2/NFKB1 signaling pathwayNuclear factor erythroid 2-related factor 2 / Nuclear factor kappa B axis

Pharmacological modulation typically involves the activation of Nrf2 to induce antioxidant enzymes (e.g., HO-1, NQO1) while simultaneously inhibiting NF-κB signaling to suppress pro-inflammatory cytokine production (e.g., IL-6, TNF-α) [1, 2]. This is often achieved through Keap1 inhibition, which stabilizes Nrf2, or through IKK complex inhibition, which prevents NF-κB translocation [3, 4].