Aberrant NRF2-Dependent Cytoprotection Subverts Stress Homeostasis and Promotes Tumor Progression

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) coordinates antioxidant defense, metabolism, iron homeostasis, and proteostasis to support cellular adaptation to stress. Kelch-like ECH-associated protein 1 (KEAP1)-Cullin 3 (CUL3) continuously targets NRF2 for proteasomal degradation. Oxidative or electrophilic stress modifies sensor cysteines in KEAP1, transiently attenuating degradation and allowing NRF2 to stabilize and accumulate in the nucleus. Complementary KEAP1-independent mechanisms limit excessive or prolonged NRF2 activity, including glycogen synthase kinase 3 (GSK3)/β-transducin repeat-containing protein (β-TrCP)-mediated degradation and SMAD-specific E3 ubiquitin-protein ligase 2 (SMURF2)-mediated nuclear clearance. In cancer, genetic, epigenetic, and signaling alterations can disable these restraints and sustain NRF2 activity. Persistent NRF2 signaling increases cancer-cell stress tolerance by supporting antioxidant defense, metabolic adaptation, proteostasis, and resistance to therapy. This review examines the spatial and context-dependent control of NRF2 by KEAP1-CUL3, GSK3/β-TrCP, and SMURF2 and considers how failure to terminate cytoprotective signaling supports tumor progression.