The Role of Nrf2 in the Cell's Antioxidant Response to Medical Ozone (2019 Review)

September 20, 2026

Background

By 2019 the idea that medical ozone works through a mild, controlled oxidative stress was well established among researchers in the field. What was less clear was the machinery inside the cell that turns that brief stress into a lasting protective response. The leading candidate was Nrf2 (nuclear factor erythroid 2-related factor 2), a protein that controls the cell's antioxidant defences. This review, by Mirco Galiè and Manuela Malatesta of the University of Verona with Viviana Covi and Gabriele Tabaracci of the San Rocco Clinic in Montichiari, Italy, brings together what was known.

Study design

This is a narrative review published open access in the International Journal of Molecular Sciences. It summarises cell-culture experiments (several from the authors' own laboratory), animal studies and the small number of human studies available. It did not follow a systematic search method. The work was funded by the University of Verona and the authors declared no conflicts of interest.

Findings

How the switch works. In a resting cell, Nrf2 is held in the cytoplasm by a partner protein called Keap1 and is broken down within minutes of being made. A mild oxidative signal alters Keap1 so that it lets go. Nrf2 then moves into the nucleus and switches on genes that carry a DNA sequence known as the antioxidant response element. More than 200 such genes have been identified.

Evidence that ozone activates it. In cell studies, ozonated serum activated Nrf2 in blood-vessel lining cells in a dose-dependent way, and the authors' own work showed that mild ozone exposure increased the amount of Nrf2 at active gene sites in the nucleus. In animals, ozone raised Nrf2 and antioxidant enzymes and lowered NF-kB-driven inflammation in models of kidney disease, pancreatic damage and injury from interrupted blood supply. In people, the review cites two studies: systemic ozone in healthy volunteers raised Nrf2 in circulating white blood cells along with superoxide dismutase and catalase activity, and rectal insufflation in people with multiple sclerosis increased the activated form of Nrf2.

What Nrf2 goes on to do. The review groups its effects into several areas. It drives production of antioxidant enzymes, including those that make and recycle glutathione, and haem oxygenase-1. It supports the clearing of damaged proteins. It promotes the formation and upkeep of mitochondria, the cell's energy producers. And it turns down inflammatory genes such as IL-6 and IL-1 beta, working in opposition to NF-kB. The authors also describe effects of low ozone concentrations on fat-derived stem cells that may be relevant to tissue repair.

The cancer question. The authors give a full section to a caution. In healthy cells Nrf2 helps prevent DNA damage. But in established tumours, persistently over-active Nrf2 has been shown to support tumour growth and resistance to treatment. Because people with cancer are among those who receive ozone therapy, the authors describe this as a crucial issue that has not been resolved.

What the authors concluded

The authors conclude that Nrf2 activation is likely to explain the benefits reported for low-dose ozone in conditions where oxidative stress and inflammation are central. They suggest it does so by keeping the cell's oxidant balance steady - protecting DNA, maintaining protein quality and mitochondrial function, and restraining inflammation. They add that the Nrf2 network is too complex to allow a complete molecular model yet.

Limitations of this study

This is a narrative review without a systematic search, so the selection of studies reflects the authors' judgement. Two of the four authors are based at a private clinic; the paper declares no conflicts of interest.

Most of the evidence comes from cell cultures and animal models. The human evidence at the time amounted to two small studies that measured Nrf2 in blood cells - they show the switch is activated, not that patients' health outcomes improved as a result.

The review establishes the difference between a mild, beneficial oxidative signal and a damaging one, but does not define dose thresholds for different uses.

This review concerns a cellular mechanism. It does not establish ozone as a treatment or cure for cancer itself, and the authors' own caution about Nrf2 in tumours is unresolved. Ozone therapy is a complementary approach and should always be discussed with your oncology team.