From Antagonism to Coexistence: NRF2/NF-κB Co-Activation in Cancer under Chronic Stress

José Manuel Pérez de la Lastra^1,*, Celia María Curieses Andrés², Elena Bustamante Munguira², Celia Andrés Juan³, Eduardo Pérez-Lebeña⁴
1 Institute of Natural Products and Agrobiology, CSIC-Spanish Research Council, Avda. Astrofísico Fco. Sánchez, 3, La Laguna, Spain
2 Hospital Clínico Universitario de Valladolid, Avenida de Ramón y Cajal, 3, Valladolid, Spain
3 Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University, Paseo de Belén, 7, Valladolid, Spain
4 Sistemas de Biotecnología y Recursos Naturales, Valladolid, Spain
* Corresponding Author: José Manuel Pérez de la Lastra. Email: email
(This article belongs to the Special Issue: Advances in Nrf2 Signaling Pathway in Neurodegenerative Diseases)

BIOCELL https://doi.org/10.32604/biocell.2026.080867

Received 17 February 2026; Accepted 25 May 2026; Published online 15 June 2026

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Abstract

Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and Nuclear Factor kappa B (NF-κB) are central regulators of redox balance and inflammation, and in healthy tissues, their activities are tightly coordinated. Classical models emphasise an antagonistic relationship in which NRF2-driven antioxidant programmes limit the oxidative cues that sustain NF-κB signalling, while inflammatory cascades can restrain cytoprotective responses when robust host defence is required. Increasing evidence from experimental systems and human tumours indicates that this antagonism is frequently relaxed in cancer. Chronic exposure to reactive oxygen species (ROS), cytokines, hypoxia, and mechanical distortion reconfigures the shared regulatory module formed by these transcription factors, allowing stable co-activation rather than mutual exclusion. In many malignancies, NRF2 and NF-κB become simultaneously active, generating hybrid transcriptional states that integrate antioxidant, inflammatory, metabolic, and survival programmes within the same tumour ecosystem.

Keywords

Nuclear factor erythroid 2-related factor 2; nuclear factor kappa B; redox signalling; inflammation; cancer; transcriptional crosstalk; tumour microenvironment; chronic stress; hybrid activation states

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From Antagonism to Coexistence: NRF2/NF-κB Co-Activation in Cancer under Chronic Stress

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