TY  - EJOU
AU  - Lastra, José Manuel Pérez de la 
AU  - Andrés, Celia María Curieses 
AU  - Munguira, Elena Bustamante 
AU  - Juan, Celia Andrés 
AU  - Lebeña, Eduardo Pérez 

TI  - NRF2 Insufficiency in Chronic Disease
T2  - BIOCELL

PY  - 
VL  - 
IS  - 
SN  - 1667-5746

AB  - 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.
KW  - 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

DO  - 10.32604/biocell.2026.080868