KEAP1-Nrf2 Signaling in Chronic Inflammatory Disorders: Integrating Redox Biology, Quantitative Evidence, and Precision Therapeutics.

BACKGROUND: Chronic inflammatory disorders represent a major global health burden characterized by persistent immune activation, oxidative stress, and progressive tissue dysfunction. Dysregulated redox signaling has positioned the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis as an emerging therapeutic target. METHODS: This review critically examines the mechanistic architecture and context-dependent regulation of KEAP1-Nrf2 signaling across chronic inflammatory disorders, integrating disease-specific evidence, signaling crosstalk, quantitative preclinical findings, therapeutic modulators, nanoenabled delivery systems, clinical evidence, patent trends, and artificial intelligence-assisted drug discovery strategies. RESULTS: KEAP1-Nrf2 signaling extends beyond antioxidant defense to regulate immunometabolic homeostasis, mitochondrial function, inflammatory signaling, and cellular stress adaptation. Crosstalk with NF-κB, MAPK, PI3K/Akt, and inflammasome-associated pathways contributes to disease-specific inflammatory responses. Preclinical evidence supports natural and synthetic Nrf2 modulators, while nanotechnology-based approaches may improve delivery and tissue specificity. However, dose optimization, bioavailability, off-target effects, long-term safety, and patient heterogeneity remain important translational challenges. CONCLUSION: KEAP1-Nrf2 represents a context-dependent therapeutic axis with substantial potential across chronic inflammatory diseases. Integrating quantitative evidence, precision delivery, biomarker-guided approaches, and computational strategies may facilitate clinical translation while addressing risks associated with sustained pathway activation.