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Updated: Oct 28, 2026

Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
Aberrant NRF2-Dependent Cytoprotection Subverts Stress Homeostasis and Promotes Tumor Progression
Gaoqing Feng1, Yuhong Yang1, Huahua Wang1
1Advanced Technology Research Institute, State Key Laboratory of Hearing and Balance Science and Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
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.
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