“Antioxidant” is one of the most overworked words in the supplement vocabulary, and one of the least informative. The biology underneath it is real and well mapped, but it is not the biology the word implies. Cells do not simply mop up damaging molecules; they run a transcriptional programme that senses chemical threat and switches on a coordinated defence, and the master switch for that programme is a transcription factor called Nrf2.
This guide covers what oxidative stress means as a technical term, how the Keap1–Nrf2 switch works, which genes it turns on, why glutathione sits at the centre of it, and what happened when the field’s two obvious predictions — give people antioxidants, or give them an Nrf2 activator — were tested in large trials. The answers in both cases were worse than expected.
The short answer
- Oxidative stress has a technical definition, and it is not just “too many free radicals”. Helmut Sies, who introduced the term in 1985, defines it as an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.
- Nrf2 is a transcription factor, not an antioxidant. It was isolated in 1994; the gene is NFE2L2.
- Keap1 is its off-switch, and a chemical sensor. Keap1 works as an adaptor for a Cul3-based ubiquitin ligase that continuously marks Nrf2 for destruction. Reactive cysteines on Keap1 are the sensors: modify them and Nrf2 escapes.
- Freed Nrf2 switches on a battery of genes by pairing with small Maf proteins and binding the antioxidant response element. The list includes NQO1, heme oxygenase-1, and the genes for making glutathione.
- Glutathione is the main thing this programme builds. It is a tripeptide with an unusual gamma-linkage, made in two ATP-dependent steps, present at roughly 1 to 5 millimolar inside cells and around 10 millimolar in liver.
- Antioxidant supplement trials went badly. In SELECT, vitamin E significantly increased the risk of prostate cancer among healthy men. Beta-carotene trials in smokers increased lung cancer.
- So did the obvious Nrf2 drug. The BEACON trial of bardoxolone methyl was terminated: 96 patients in the treatment group were hospitalized for or died from heart failure versus 55 on placebo, a hazard ratio of 1.83.
- Nrf2 activation is not simply beneficial. Tumours carrying KEAP1 or NFE2L2 mutations use constitutive Nrf2 activity to resist chemotherapy.
- The GHK-Cu Nrf2 claim does not hold up. There is no published functional study linking GHK or GHK-Cu to Nrf2; the circulating claim traces to a single mislabelled table row in a re-analysis of two cancer cell lines.
Nrf2 and the Keap1–Nrf2–ARE pathway
NF-E2-related factor 2 · gene NFE2L2 · the antioxidant response element pathway
- Molecule type
- Basic leucine-zipper transcription factor — a DNA-binding protein, not an antioxidant molecule
- Isolated
- 1994, by Moi, Chan, Asunis, Cao and Kan, as a NF-E2-like bZIP activator
- Repressor
- Keap1, identified in 1999 as binding the Neh2 domain and repressing nuclear activation of antioxidant response elements
- Degradation route
- Keap1 acts as an adaptor for a Cul3-based E3 ubiquitin ligase; Nrf2 is continuously ubiquitinated and destroyed by the proteasome
- Sensor chemistry
- Reactive cysteine sulfhydryl groups on Keap1
- DNA partner
- Small Maf proteins, via the Neh1 domain; the complex binds the antioxidant response element (ARE)
- Representative targets
- NQO1, heme oxygenase-1, the glutamate-cysteine ligase subunits GCLC and GCLM, glutathione synthetase, the cystine transporter xCT
- Approved drugs touching it
- Dimethyl fumarate and omaveloxolone, both authorized in Canada — though neither label claims Nrf2 as an established mode of action
Where the evidence stands
- Cell studies
- Animal studies
- Large human trials, including failures
- Approved drugs for specific diseases
The pathway is well established. “Activating Nrf2 is good for you” is not; the large trials that tested versions of that idea went the wrong way.
What oxidative stress actually means
The term has a specific author and a specific definition. Helmut Sies introduced “oxidative stress” in a 1985 book of that name, and his 2020 paper in Antioxidants gives the current formulation: an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.
Two things in that sentence are easy to miss. The first is “disruption of redox signaling and control”, which is not the same as damage. Reactive oxygen species are not purely destructive; cells use them as signals, and interfering with that signalling is a distinct kind of problem from oxidising a membrane. The second is “imbalance”, which cuts both ways. The same literature now recognises reductive stress — too far in the other direction — alongside the distinction Sies draws between oxidative eustress, which is useful, and oxidative distress, which is not.
This is why “more antioxidants is better” was never a sound inference from the biology, and why, as the trials below show, it did not survive testing.
What Nrf2 is
Nrf2 is a transcription factor: a protein that binds DNA and changes which genes are read. It is not itself an antioxidant and does not neutralise anything. Its job is to turn on the genes for the proteins that do.
It was isolated in 1994 by Moi, Chan, Asunis, Cao and Kan, who published it in PNAS as NF-E2-related factor 2 — a NF-E2-like basic leucine zipper transcriptional activator binding the tandem NF-E2/AP1 repeat of the beta-globin locus control region. The name records what it was found next to rather than what it turned out to do, which is a common pattern in gene naming; the same thing happened with mTOR.
The Keap1 switch
The most elegant feature of this system is that it is held off by default, at considerable expense, so that it can be released instantly.
In 1999 Itoh and colleagues reported in Genes & Development that Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. The mechanism was filled in over the following five years. Keap1 functions as an adaptor for a Cul3-based E3 ubiquitin ligase, as Kobayashi and colleagues showed in 2004, continuously tagging Nrf2 with ubiquitin so the proteasome destroys it. In unstressed cells, Nrf2 is being made and immediately thrown away.
What releases it is chemistry rather than a signalling cascade. Keap1 carries reactive cysteine residues, and these are the sensors. Dinkova-Kostova and colleagues reported direct evidence in 2002 that the sulfhydryl groups of Keap1 are the sensors regulating induction of the phase 2 enzymes, and Zhang and Hannink showed in 2003 that distinct cysteines are required for Keap1-dependent ubiquitination of Nrf2 and for its stabilisation by chemopreventive agents and oxidative stress. Electrophiles and oxidants modify those cysteines; Keap1 can no longer deliver Nrf2 to the ligase; Nrf2 accumulates and goes to the nucleus.
What Nrf2 turns on
In the nucleus, Nrf2 heterodimerizes with small Maf proteins through its Neh1 domain and binds the antioxidant response element located within the promoter region of specific target genes. The gene battery that follows is the actual defence system.
| Target | What it does |
|---|---|
| NQO1 | Quinone oxidoreductase — the classic phase 2 detoxification readout, and the standard assay for Nrf2 activity |
| Heme oxygenase-1 | Breaks down heme; the other canonical Nrf2 readout |
| GCLC and GCLM | The catalytic and modifier subunits of glutamate-cysteine ligase — the rate-limiting enzyme of glutathione synthesis |
| Glutathione synthetase | The second enzyme of glutathione synthesis |
| xCT | The glutamate/cystine antiporter that brings in the cysteine glutathione needs |
| Thioredoxin | A separate protein-based reducing system working in parallel to glutathione |
| G6PD | Feeds the pentose phosphate pathway, which supplies the NADPH that keeps glutathione reduced |
Note the shape of that list. Nrf2 does not produce a radical scavenger; it builds capacity — the enzymes, the transporter for the raw material, and the reducing power to recharge the system. A 2025 study in astrocytes puts the glutathione connection directly: Nrf2 regulates the basal production of glutathione through constitutive transcriptional regulation of glutamate-cysteine ligase and xCT, and names GCLC, GCLM and glutathione synthetase as the key synthetic enzymes.
Glutathione, the main product
Glutathione is the molecule most of this machinery exists to make, and it is a peptide — which is why it sits in a research-reagent catalogue at all.
Chemically it is L-γ-glutamyl-L-cysteinyl-glycine: three amino acids, formula C10H17N3O6S, average molecular weight 307.3. The interesting part is the gamma in the name. In an ordinary peptide, the bond runs from the alpha-carboxyl group of one residue to the amino group of the next. In glutathione, the ligase joins the gamma-carboxyl group of glutamate to the amino group of cysteine. That unusual linkage appears to act as protection against the peptidases abundant in blood plasma — a source of real stability, and a reason glutathione does not behave like a normal tripeptide. Our explainer on dipeptides, tripeptides and oligopeptides covers the ordinary case for comparison.
It is built in two sequential ATP-dependent steps. Glutamate-cysteine ligase does the first and is rate-limiting, competitively inhibited by glutathione itself — a clean feedback loop. Glutathione synthetase adds the glycine. Concentrations are high for a metabolite: a 2023 review gives roughly 1 to 5 millimolar in cells generally, with liver the highest in the body, reaching about 10 millimolar. The normal ratio of reduced to oxidised glutathione is around 100 to 1, which is what makes that ratio a usable readout of a cell’s redox state.
A figure worth getting right. “Glutathione is present at about 10 millimolar in cells” is a common overstatement. Ten millimolar is the hepatic high end; the general cellular range reported is 1 to 5 millimolar.
What happened in the antioxidant trials
If oxidative damage causes disease and antioxidants prevent oxidative damage, supplementing antioxidants should prevent disease. That hypothesis was tested properly, at scale, and it failed — in some cases by causing harm.
The clearest single result is SELECT, the Selenium and Vitamin E Cancer Prevention Trial, published in JAMA in 2011. In 34,887 men in the primary analysis, 620 in the vitamin E group developed prostate cancer against 529 on placebo, a hazard ratio of 1.17 with a 99% confidence interval of 1.004 to 1.36 and a P value of .008. The authors’ conclusion is unambiguous: dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.
Before that, two beta-carotene trials had gone the same way. The ATBC trial, published in the New England Journal of Medicine in 1994, and CARET, published there in 1996, both studied beta-carotene in populations of smokers and asbestos-exposed workers. The US National Cancer Institute’s summary of the results records that ATBC found an increased incidence of lung cancer among those who took beta-carotene supplements, and that CARET found an increased risk of lung cancer and increased death from all causes, with the trial ended early and the higher risks persisting on later follow-up.
These results are the reason the field moved from “antioxidants” to redox signalling. If reactive species are also messengers, blanket suppression is not obviously beneficial, and may remove signals a tissue needs. Our guide to clinical trial phases covers why a hypothesis can look strong through phase 2 and fail at scale.
The drugs that touch this pathway
Two approved medicines are routinely described as Nrf2 activators. Both are authorized in Canada, and in both cases the regulator’s own language is more careful than the secondary literature’s.
Dimethyl fumarate was approved for relapsing forms of multiple sclerosis, with the FDA label dated March 2013 and Health Canada issuing a Notice of Compliance to Biogen Idec Canada on 3 April 2013, under Drug Identification Number 02404508 for the lower strength and 02420201 for the higher. The label states that dimethyl fumarate and its active metabolite activate the Nrf2 pathway, and that the Nrf2 pathway is involved in the cellular response to oxidative stress. It also states, in terms: the mechanism by which dimethyl fumarate exerts its therapeutic effect in multiple sclerosis is unknown. Nrf2 activation is a demonstrated pharmacological effect of the drug, not an established mode of action.
Omaveloxolone was approved in the United States in February 2023 for Friedreich’s ataxia in patients aged 16 and over, and authorized in Canada on 13 March 2025, sponsored by Biogen Canada under Drug Identification Number 02556219. The FDA review presents its mechanism as the applicant’s postulate — that omaveloxolone activates Nrf2, which regulates the cellular response to oxidative stress — with ferritin used as a pharmacodynamic marker of Nrf2 activation.
Bardoxolone methyl is the cautionary tale. It is a potent Nrf2 activator, and the BEACON trial tested it in 2,185 patients with type 2 diabetes and stage 4 chronic kidney disease, publishing in the New England Journal of Medicine in 2013. The trial was stopped on the data and safety monitoring committee’s recommendation. On the primary outcome there was no benefit: 69 events in each group, hazard ratio 0.98. On harm there was a clear signal: 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group, hazard ratio 1.83, 95% confidence interval 1.32 to 2.55, P less than 0.001. The authors’ conclusion records that a higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial.
The other side of Nrf2
There is a structural reason to be wary of “activate Nrf2” as a goal, and it comes from cancer biology. If Nrf2 makes cells better at surviving chemical insult, then a tumour that switches it on permanently becomes better at surviving chemotherapy.
That is what happens. A 2006 study in PLOS Medicine found somatic KEAP1 mutations in non-small-cell lung cancer at a frequency of 50% in cell lines and 19% in tumours, concluded that biallelic inactivation of KEAP1 is a frequent genetic alteration in the disease, and reported that reduced chemosensitivity of cancer cells with high Nrf2 activity suggests Nrf2 contributes to drug resistance. Mutations on the other side of the switch do the same thing: a 2008 PNAS paper showed that cancer-related mutations in Nrf2 impair its recognition by the Keap1–Cul3 ligase and promote malignancy. A 2020 review summarises the clinical picture, describing tumours with constitutive or prolonged Nrf2 activation as exhibiting an aggressive phenotype characterised by therapy resistance and unfavorable prognosis.
So the pathway is context-dependent in the same way AMPK turned out to be: protective in a healthy cell facing an insult, helpful to a tumour already established. Anyone presenting Nrf2 activation as unambiguously good is leaving out half the literature.
Where peptides fit — and the GHK-Cu claim
Glutathione: a genuine connection
Glutathione is the one unambiguous link between this pathway and a peptide reagent. It is a tripeptide, Nrf2 controls the genes that make it, and the reduced-to-oxidised ratio is the standard readout of cellular redox state. Nothing about that requires overstatement.
On supplementation the honest position is narrow. One 6-month randomised, double-blinded, placebo-controlled trial in 54 non-smoking adults reported that oral glutathione raised glutathione by 30 to 35% in erythrocytes, plasma and lymphocytes and by 260% in buccal cells in the high-dose group. That is a real result, and it is also a single small trial funded by the company that supplied the glutathione, with the lead author reporting research support from that manufacturer. Neither “oral glutathione does nothing” nor “oral glutathione works” is well supported; one small industry-funded trial is what exists.
GHK-Cu and Nrf2: the claim does not hold up
GHK-Cu is widely described online as an Nrf2 activator. We went looking for the primary evidence, and it is not there.
The claim traces to two review papers by Loren Pickart and colleagues, from 2015 in Cosmetics and 2018 in the International Journal of Molecular Sciences. Neither is an experiment. The gene data in them are a re-analysis of the Broad Institute’s Connectivity Map, holding three GHK profiles — two from the PC3 prostate-cancer cell line and one from the MCF7 breast-cancer cell line. Not fibroblasts, not skin, and not the authors’ own experiments.
On Nrf2 specifically: the 2018 paper does not mention Nrf2 or NFE2L2 at all. In the 2015 paper, NFE2L2 appears once, in a table, and it is mislabelled there as “nuclear respiratory factor 2” — a different protein entirely from nuclear factor erythroid 2-related factor 2. The body text never discusses it. There is no functional validation of any kind.
The authors are also appropriately described: all of them are affiliated with Skin Biology, a copper-peptide company, and the 2018 paper recommends developing GHK-based products, while both papers declare no conflict of interest. Their own hedging is worth quoting as a model of what the secondary literature drops: the 2015 review proposes interaction with antioxidant-related genes as a possible explanation of its antioxidant activity, says the exact mechanism of its actions remains to be established, and states that there is not enough information to establish a clear relationship between the expression changes and the biological effects.
What the 2018 paper does report, and what is a different and more defensible kind of claim, concerns enzyme activity in animals rather than gene expression: treatment of wounds with GHK leading to elevated antioxidant enzyme levels, increased superoxide dismutase activity in mice with acute lung injury, and higher glutathione and ascorbic acid levels in rats treated with a GHK collagen dressing. Our GHK-Cu research guide covers what the compound has and has not been shown to do.
Copper, separately
There is a real copper–antioxidant connection that has nothing to do with Nrf2. As the US National Institutes of Health’s Office of Dietary Supplements sets out, copper is a cofactor for several cuproenzymes; defence against oxidative damage depends mainly on the copper-containing superoxide dismutases, and ceruloplasmin carries more than 95% of the total copper in healthy human plasma while participating in iron metabolism. That is the honest version of “copper matters for antioxidant defence” — enzyme cofactor chemistry, not transcription factor activation.
NAD+ and sirtuins: thin
A SIRT1–Nrf2 interaction appears in the literature, but it is unsettled. A 2025 review notes evidence that acetylation increases Nrf2 activity while deacetylation reduces it, alongside other results showing that activating the SIRT1 deacetylase increases Nrf2 activity, observes that different groups’ results sometimes contradict each other, and frames the feedback loop as possible in its own title. We found no source establishing a direct NAD+-to-Nrf2 link. Our guides to NAD+ and sirtuins cover that axis on its own terms.
What’s established and what isn’t
Reasonably well established
- Nrf2 is a bZIP transcription factor encoded by NFE2L2, isolated in 1994.
- Keap1 represses it, acting as the adaptor for a Cul3-based ubiquitin ligase that drives continuous proteasomal degradation of Nrf2.
- Reactive cysteines on Keap1 are the chemical sensors of the system.
- Freed Nrf2 pairs with small Maf proteins and binds the antioxidant response element, switching on NQO1, heme oxygenase-1, GCLC, GCLM, glutathione synthetase and xCT.
- Glutathione is γ-glutamyl-cysteinyl-glycine, made in two ATP-dependent steps with glutamate-cysteine ligase rate-limiting, at roughly 1–5 mM in cells and about 10 mM in liver, with a reduced-to-oxidised ratio around 100:1.
- Vitamin E significantly increased prostate cancer risk in SELECT; beta-carotene increased lung cancer in ATBC and CARET.
- BEACON was terminated with a heart-failure hazard ratio of 1.83 for bardoxolone methyl and no benefit on the primary outcome.
- Constitutive Nrf2 activation in tumours is associated with chemoresistance and poor prognosis.
Open questions
- Whether Nrf2 activation can be therapeutic outside the two approved, narrow indications. Neither of those labels claims Nrf2 as an established mode of action.
- Whether dimethyl fumarate’s benefit in multiple sclerosis has anything to do with Nrf2. The regulators say the mechanism is unknown.
- Whether there is a safe therapeutic window for Nrf2 activation given the BEACON result and the tumour-resistance literature.
- Whether oral glutathione supplementation does anything useful. One small manufacturer-funded trial reported raised glutathione; nothing larger has confirmed it.
- Whether SIRT1 and Nrf2 regulate each other. A 2025 review describes the evidence as contradictory and the feedback loop as hypothetical.
- Whether GHK or GHK-Cu interacts with Nrf2 at all. No functional study exists; the only trace is one mislabelled table row in a cancer-cell-line re-analysis.
Sourcing redox reagents in Canada
Redox work has one documentation problem the rest of peptide research does not: the analyte is often unstable in exactly the way the experiment is about.
- Glutathione oxidises. Reduced glutathione going to the oxidised dimer is the reaction the whole field measures, and it happens in a vial as readily as in a cell. A certificate tells you what the material was when tested, not what it is after a month in a warm drawer. See how peptides degrade.
- Check purity and identity separately, with HPLC for how much of the material is the peak you want and mass spectrometry for whether that peak is the right molecule.
- Match the batch number on the certificate to the vial, which our COA guide covers, along with how to tell a genuine certificate from a decorative one.
- Keep material cold, dry and dark, lyophilized until needed — see the storage guide and what lyophilized means.
Glutathione (GSH)The tripeptide the Nrf2 gene battery exists to buildView product
GHK-CuOften described as an Nrf2 activator; no functional study supports thatView product
NAD+A separate redox pool; no direct NAD+-to-Nrf2 link is establishedView product
Research use only. Pure Peptides Canada products are laboratory reagents for in-vitro research, not for human or veterinary use. This article explains published research for education; it is not medical, dietary or dosing guidance.
Frequently asked questions
What is Nrf2?
Nrf2 is a basic leucine-zipper transcription factor encoded by the gene NFE2L2. It was isolated in 1994 as NF-E2-related factor 2. It is not itself an antioxidant and neutralises nothing; its role is to switch on a battery of genes for the enzymes and transporters that make up a cell’s chemical defence system, including the genes for synthesising glutathione.
How does the Keap1-Nrf2 pathway work?
In an unstressed cell, Keap1 binds Nrf2 and acts as an adaptor for a Cul3-based ubiquitin ligase that continuously tags Nrf2 for destruction by the proteasome, so Nrf2 is made and immediately thrown away. Keap1 carries reactive cysteine residues that act as chemical sensors. Electrophiles and oxidants modify those cysteines, Keap1 can no longer deliver Nrf2 for degradation, and Nrf2 accumulates, enters the nucleus, pairs with a small Maf protein and binds the antioxidant response element in its target genes.
What is oxidative stress?
Helmut Sies, who introduced the term in 1985, defines it as an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage. Two parts of that are often dropped: disruption of redox signalling is distinct from molecular damage, because reactive species also act as messengers, and an imbalance can run in the other direction, which the same literature calls reductive stress.
Why is glutathione relevant to Nrf2?
Because the Nrf2 gene battery is largely a glutathione-building programme. Nrf2 controls GCLC and GCLM, the two subunits of glutamate-cysteine ligase, which is the rate-limiting enzyme of glutathione synthesis; it also controls glutathione synthetase and xCT, the transporter that brings in the cysteine the pathway needs. Glutathione itself is the tripeptide gamma-glutamyl-cysteinyl-glycine, present at roughly 1 to 5 millimolar in cells and about 10 millimolar in liver.
Why is glutathione called a gamma-glutamyl peptide?
Because of where the first peptide bond is. In an ordinary peptide the bond runs from the alpha-carboxyl group of one residue to the amino group of the next; in glutathione, the ligase joins the gamma-carboxyl group of glutamate to the amino group of cysteine instead. That unusual linkage appears to protect the molecule from the peptidases abundant in blood plasma, which is why glutathione does not behave like a typical tripeptide.
Did antioxidant supplements work in large trials?
No, and some caused harm. In the SELECT trial, published in JAMA in 2011, 620 of the men taking vitamin E developed prostate cancer against 529 on placebo, a hazard ratio of 1.17, and the authors concluded that dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. The ATBC and CARET beta-carotene trials increased lung cancer, and CARET was ended early with an increased risk of lung cancer and increased death from all causes.
Does GHK-Cu activate Nrf2?
There is no published functional evidence that it does. The claim traces to two review papers whose gene data are a re-analysis of Connectivity Map profiles from two cancer cell lines, PC3 and MCF7, rather than the authors’ own experiments. The 2018 paper does not mention Nrf2 at all, and in the 2015 paper NFE2L2 appears once, in a table, mislabelled as nuclear respiratory factor 2, with no discussion in the text and no functional validation. All the authors are affiliated with a copper-peptide company.
Redox research reagents, documented by batch
Glutathione, GHK-Cu, NAD+ and the rest of the range, priced in Canadian dollars and shipped tracked from inside Canada.
References
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- The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029–1035. DOI
- Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150–1155. DOI
- Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86. DOI
- Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002;99(18):11908–11913. DOI
- Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003;23(22):8137–8151. DOI
- Kobayashi A, Kang M-I, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004;24(16):7130–7139. DOI
- Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1–NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):e420. DOI
- Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA. 2008;105(36):13568–13573. DOI
- Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549–1556. DOI
- de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492–2503. DOI
- Lu SC. Glutathione synthesis. Biochim Biophys Acta Gen Subj. 2013;1830(5):3143–3153. DOI
- Pickart L, Vasquez-Soltero JM, Margolina A. GHK-Cu may prevent oxidative stress in skin by regulating copper and modifying expression of numerous antioxidant genes. Cosmetics. 2015;2(3):236–247. DOI
- Richie JP Jr, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD, Muscat JE. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251–263. DOI
- Pickart L, Margolina A. Regenerative and protective actions of the GHK-Cu peptide in the light of the new gene data. Int J Mol Sci. 2018;19(7):1987. DOI
- Sies H. Oxidative stress: concept and some practical aspects. Antioxidants. 2020;9(9):852. DOI
- Panieri E, Buha A, Telkoparan-Akillilar P, et al. Potential applications of NRF2 modulators in cancer therapy. Antioxidants. 2020;9(3):193. DOI
- Georgiou-Siafis SK, Tsiftsoglou AS. The key role of GSH in keeping the redox balance in mammalian cells: mechanisms and significance of GSH in detoxification via formation of conjugates. Antioxidants. 2023;12(11):1953. DOI
- Ikeda Y, Fujii J. The emerging roles of γ-glutamyl peptides produced by γ-glutamyltransferase and the glutathione synthesis system. Cells. 2023;12(24):2831. DOI
- He J, Hewett SJ. Nrf2 regulates basal glutathione production in astrocytes. Int J Mol Sci. 2025;26(2):687. DOI
- Gureev AP, Krutskikh EP. Regulation of the NRF2 transcription factor activity via SIRT1-induced deacetylation: possible SIRT1–NRF2 feedback loop. Russ J Genet. 2025;61(2):3–11. DOI
- Human Metabolome Database, entry HMDB0000125 (glutathione): formula C10H17N3O6S, average molecular weight 307.323.
- US National Cancer Institute. Antioxidants and cancer prevention (fact sheet), summarising the ATBC, CARET and SELECT results.
- US Food and Drug Administration. TECFIDERA (dimethyl fumarate) prescribing information, March 2013, including the statement that the therapeutic mechanism in multiple sclerosis is unknown.
- Health Canada. Summary Basis of Decision, Tecfidera; Notice of Compliance issued to Biogen Idec Canada Inc. on 3 April 2013; DIN 02404508 and 02420201.
- US Food and Drug Administration. SKYCLARYS (omaveloxolone), NDA 216718, summary review memorandum dated 28 February 2023.
- Health Canada. Regulatory Decision Summary, Skyclarys (omaveloxolone); authorized 13 March 2025, Biogen Canada Inc., DIN 02556219.
- Health Canada. Public advisory RA-75003, “Unauthorized injectables and other health products from Galena Pharm Inc. pharmacy may pose serious health risks”, 12 February 2021.
- US National Institutes of Health, Office of Dietary Supplements. Copper: fact sheet for health professionals, updated 18 October 2022.
For laboratory research use only. Not for human or veterinary use. This article summarizes published research for educational purposes and is not medical advice.