What is it about?
Cells constantly face chemical and oxidative stress. One of their main defense systems is the NRF2-KEAP1 pathway. This pathway is usually described as an “antioxidant switch”: stress turns NRF2 on, NRF2 activates protective genes, and the cell returns to normal. This article argues that the pathway is more sophisticated than that. NRF2-KEAP1 behaves more like a stress-control circuit. It does not simply turn protection on or off. It senses stress, measures how strong and how long the signal lasts, activates a graded response, and then helps shut that response down when the problem is resolved. The key idea is resolution. Short-term NRF2 activation can protect cells. But if the signal stays active for too long, or if the system cannot reset properly, the same pathway may contribute to cancer, fibrosis, metabolic disease, or other forms of pathology.
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Why is it important?
NRF2 is often treated as something we should activate to protect cells from damage. That view is incomplete. This review suggests that the real biological question is not only whether NRF2 is activated, but whether the signal is properly resolved. A pathway that protects cells during short stress may become harmful when its feedback and termination systems fail. This matters for drug development and disease biology. Instead of simply trying to boost NRF2 activity, future therapies may need to restore normal signaling dynamics: sensing, activation, feedback, turnover, and reset. This shift could help explain why NRF2 activation is beneficial in some settings but harmful in others.
Perspectives
I wrote this paper to explain why the traditional “antioxidant switch” model does not fully capture NRF2 biology. I propose that NRF2–KEAP1 functions as a control circuit in which timing, feedback, and signal resolution are as important as activation itself. The key message is that many diseases may arise not because NRF2 turns on, but because the system fails to reset properly.
Ardie Barry Sailis
University of Malaya
Read the Original
This page is a summary of: NRF2–KEAP1 as a redox signal-resolution circuit: Beyond the antioxidant switch, Progress in Biophysics and Molecular Biology, June 2026, Elsevier,
DOI: 10.1016/j.pbiomolbio.2026.03.005.
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