NRF2 Insufficiency in Chronic Disease

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, Intensive Care Unit, 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

BIOCELL https://doi.org/10.32604/biocell.2026.080868

Received 24 February 2026; Accepted 25 June 2026; Published online 08 July 2026

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Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) orchestrates antioxidant defence, electrophile detoxification, and stress recovery across tissues. This paper frames chronic disease vulnerability through the lens of NRF2 insufficiency, defined as reduced functional output of the antioxidant response element programme. We describe the mechanisms that blunt NRF2 signalling, including genetic variation in NFE2L2 and Keap1, epigenetic repression, post-translational degradation routes, and cumulative exposome pressures. Downstream consequences include impaired glutathione-centred buffering, mitochondrial dysfunction, proteostasis failure, inflammatory amplification, and heightened susceptibility to regulated cell death. Using an organ-by-endotype approach, we map recurring patterns across lung, liver, and metabolic tissues, cardiovascular and renal systems, brain, and barrier interfaces that shape systemic ageing phenotypes. Practical biomarkers are reviewed alongside lifestyle and exposome modification strategies, nutritional and nutraceutical approaches, and pharmacological interventions. Preclinical and human evidence for outcome improvement with NRF2 restoration is evaluated, and a risk-management framework addressing boundary conditions such as cancer progression and therapy resistance is proposed. We close with a research agenda prioritising causal study designs, reproducible scoring, and clinically meaningful endpoints to guide precision modulation of NRF2 in chronic disease.

Keywords

Nuclear factor erythroid 2-related factor 2; Kelch-like ECH-associated protein 1; oxidative stress; antioxidant response element; redox homeostasis; detoxification; inflammation; mitochondrial dysfunction; precision medicine

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NRF2 Insufficiency in Chronic Disease

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