Review article

NRF2–KEAP1 as a redox signal-resolution circuit: Beyond the antioxidant switch

The problem with the “switch” model

For years, NRF2 has been framed as a binary defense mechanism. Under stress, it turns “on,” activates antioxidant genes, and then returns to baseline once the threat is gone. This model has been useful, but it leaves key observations unexplained.

Across many systems, transient NRF2 activation is consistently protective. Yet sustained activation is linked to cancer progression, fibrosis, and metabolic dysfunction. If NRF2 were just a switch, the expectation would be straightforward: more activation, more protection. But that is not what we observe. Instead, similar levels of NRF2 activation can produce very different outcomes depending on how long the signal lasts.

This inconsistency led us to reconsider a basic assumption: what if NRF2 signaling is not defined by whether it turns on, but by how it resolves?

A different perspective: NRF2 as a “redoxostat”

In our paper, we propose that NRF2–KEAP1 functions as a redox signal-resolution circuit, or what we term a redoxostat.

Rather than a binary switch, this system behaves more like a control circuit with four key functions:

• Detection: KEAP1 senses oxidative and electrophilic stress through reactive cysteine residues
• Integration: the system encodes both the magnitude and duration of the signal
• Response: NRF2 activates a graded transcriptional program
• Resolution: the system actively terminates signaling and restores baseline

This last step, resolution, is central.

In many biological systems, resolution is not passive. It requires coordinated processes, including protein turnover, feedback regulation, and metabolic recovery. The NRF2 pathway is no exception.

Why resolution matters

One of the key insights from this framework is that biological outcomes depend more on signal duration than peak activation.

• Transient activation - adaptive, cytoprotective responses
• Sustained activation - metabolic rewiring, reductive stress, and pathology

This explains why NRF2 can be both beneficial and harmful without invoking contradictory roles. The pathway itself is not changing function. What changes is whether the signal is properly terminated. From this perspective, disease is less about “too much NRF2” and more about failure to resolve NRF2 signaling.

The hidden machinery of termination

A major part of this work involved integrating mechanisms that are often studied separately but rarely considered together. Signal resolution in the NRF2–KEAP1 system involves:

• KEAP1 resynthesis and reactivation
• Ubiquitin–proteasome-mediated degradation of NRF2
• Autophagy pathways, particularly p62-dependent regulation
• Metabolic processes that restore redox-sensitive cysteine states

These processes form what we describe as a resolution module. It is genetically encoded, energetically demanding, and tightly regulated. When any component of this module fails, NRF2 signaling persists even after the initial stress has disappeared.

A framework for understanding disease

Viewing NRF2 as a control circuit allows us to organize diverse disease mechanisms into a coherent structure.

We outline four major “failure modes”:

1. Sensor failure
   KEAP1 cannot properly detect or reset after stress
2. Controller failure
   Impaired ubiquitination leads to reduced NRF2 turnover
3. Amplifier escape
   NRF2 becomes resistant to repression due to mutations
4. Feedback failure
   Resolution mechanisms such as autophagy or metabolism are disrupted

Each of these produces sustained NRF2 signaling, but through distinct mechanisms. This helps explain why NRF2-associated pathologies appear so context-dependent.

Implications for research

One consequence of the traditional switch model is that experiments often focus on peak activation or endpoint measurements. This approach misses the temporal dimension of signaling.

If NRF2 is a dynamic control system, then key questions shift:

• How quickly does the signal rise and decay?
• How efficient is the resolution phase?
• What determines signal persistence in different tissues?

Emerging tools such as live-cell imaging, redox biosensors, and optogenetic control of signaling now make it possible to directly test these dynamics.

Implications for therapy

Most therapeutic strategies have focused on activating NRF2. This has shown benefits in some contexts, but also limitations and adverse effects.

A circuit-based view suggests a different approach:

• Instead of maximizing activation, aim to restore proper signaling dynamics
• Target mechanisms that enhance resolution, such as KEAP1 turnover or autophagic function
• Exploit metabolic dependencies created by sustained NRF2 activation in disease states

In other words, the goal is not simply to turn NRF2 on, but to ensure it can turn off appropriately.

Closing thoughts

This work is not about replacing the antioxidant switch model, but extending it. The classical view captured an essential aspect of NRF2 biology. What it missed is the importance of time. By reframing NRF2–KEAP1 as a redox signal-resolution circuit, we can reconcile its protective and pathological roles within a single framework. More broadly, this perspective suggests that stress biology is not primarily about signal strength, but about signal control. Cells must not only respond to stress, but also know when to stop.

That distinction may be where health and disease diverge.

Reference

Sailis AB. NRF2–KEAP1 as a redox signal-resolution circuit: Beyond the antioxidant switch. Progress in Biophysics and Molecular Biology. 2026;200:68–80. https://doi.org/10.1016/j.pbiomolbio.2026.03.005

Full text available here (until 2 May 2026): link