Antioxidant Defence and Nrf2

1. What This Pathway Is

The Nrf2 signalling pathway is a central regulatory mechanism of the antioxidant defence system. Under oxidative stress, Nrf2 dissociates from its inhibitor Keap1, translocates to the cell nucleus, and activates genes for antioxidant enzymes such as haem oxygenase-1, NAD(P)H quinone oxidoreductase 1, and glutathione S-transferases. These enzymes neutralise reactive oxygen species and reduce inflammatory processes. The pathway is evolutionarily conserved and plays a role in the prevention of chronic diseases, neurodegenerative processes, and ageing. Humic acid complexes and other substances can modulate this pathway by either interacting directly with Keap1 or indirectly via redox changes.

Measuring antioxidant defence in humans is challenging because it depends on individual factors such as genetics, the microbiome, and lifestyle. Laboratory findings often show clear effects, whereas human studies yield heterogeneous results. Biomarkers such as malondialdehyde, superoxide dismutase, or glutathione peroxidase are established, but their interpretation is complex. Furthermore, long-term effects are difficult to capture. Humic acid complexes, for example, demonstrate antioxidant properties in the laboratory, but controlled human studies are largely lacking to confirm these effects.

2. Which Substances Share It

All substances in the database for which this pathway is described—ordered by the extent of human testing. The numbers represent studies per type of investigation.

3. How Robust the Evidence Is

Substances such as turmeric/curcumin, probiotics, melatonin, coenzyme Q10, and zinc are well supported by controlled human studies, demonstrating consistent effects on inflammatory markers and oxidative stress parameters. Other substances, such as humic acid complexes, berberine, or frankincense, are primarily documented through laboratory and animal studies, with only a few controlled human trials. For humic acid complexes, there is evidence from cell and animal studies, but their applicability to humans remains unclear. The strength of the evidence varies widely: while some substances, such as omega-3 fatty acids or vitamin D, have been extensively studied, robust clinical evidence is lacking for others.

These substances share the ability to activate the Nrf2 signalling pathway, thereby enhancing antioxidant capacity. Many also exhibit anti-inflammatory effects, suggesting potential synergistic benefits. However, findings from laboratory studies cannot always be extrapolated to humans. For example, humic acid complexes demonstrate antioxidant and anti-inflammatory properties in vitro, but their bioavailability and efficacy in humans are scarcely investigated. A similar situation applies to adaptogens or sulforaphane, where animal studies show promise, but controlled human trials are either lacking or yield contradictory results.

4. Key Human Studies

• 1 Mediterranean Diet Reduces Inflammation in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials (2026) — Chronic inflammation
• 2 The Effect of Oleoylethanolamide (OEA) Add-On Treatment on Inflammatory, Oxidative Stress, Lipid, and Biochemical Parameters in the Acute Ischemic Str (2022) — Chronic inflammation
• 3 Effectiveness of a novel diet in attenuation of clinical activity of disease in patients with ulcerative colitis: a randomized, clinical trial (2024) — Chronic inflammation
• 4 Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: a randomized controlled trial and an (2015) — Turmeric and curcumin
• 5 Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and (2017) — Turmeric and curcumin
• 6 Reduction of delayed onset muscle soreness by a novel curcumin delivery system (Meriva®): a randomised, placebo-controlled trial (2014) — Turmeric and curcumin
• 7 Probiotic supplementation in diabetic haemodialysis patients has beneficial metabolic effects (2017) — Probiotics
• 8 The effects of probiotic supplementation on biomarkers of inflammation, oxidative stress and pregnancy outcomes in gestational diabetes (2018) — Probiotics
• 9 The effects of probiotic supplementation on mental health, biomarkers of inflammation and oxidative stress in patients with psychiatric disorders: A s (2020) — Probiotics
• 10 Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis (2014) — Melatonin
• 11 Effect of melatonin supplementation on oxidative stress parameters: A systematic review and meta-analysis (2020) — Melatonin
• 12 Impact of Melatonin Supplementation in Women with Unexplained Infertility Undergoing Fertility Treatment (2019) — Melatonin
• 13 The effects of coenzyme Q10 supplementation on metabolic profiles and mental health parameters in women with polycystic ovary syndrome (2022) — Coenzyme Q10
• 14 Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomised controlled pilot study (2023) — Coenzyme Q10
• 15 Effects of coenzyme Q10 supplementation on inflammation, angiogenesis, and oxidative stress in breast cancer patients: a systematic review and meta-analysis (2021) — Coenzyme Q10
• 16 Effects of Spirulina (Arthrospira) platensis supplementation on intestinal permeability, antioxidant and inflammatory markers, quality of life, and [further details] (2025) — Gut microbiome
• 17 Epigenetic and microbiome responses to greens supplementation in obese older adults: results from a randomised crossover-controlled trial (2026) — Gut microbiome
• 18 Weizmannia coagulans BC99 alleviates alcohol-induced oxidative stress and gut barrier dysfunction via modulation of butyrate metabolism: a randomised, [further details] (2026) — Gut microbiome
• 19 Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with [further details] (2015) — Zinc
• 20 Association of zinc deficiency with the development of cardiovascular disease events in patients with chronic kidney disease (2021) — Zinc
• 21 Effects of zinc supplementation on superoxide dismutase activity and gene expression, and metabolic parameters in overweight patients with type 2 diabetes: [further details] (2019) — Zinc
• 22 L-carnitine supplementation in the diet: a new tool in the treatment of non-alcoholic steatohepatitis—a randomised and controlled clinical trial (2010) — L-Carnitine
• 23 Effects of L-carnitine supplementation on oxidative stress and antioxidant enzyme activities in patients with coronary artery disease: a randomised, [further details] (2014) — L-Carnitine
• 24 Effect of metabolic and antioxidant supplementation on sperm parameters in oligo-astheno-teratozoospermia, with and without varicocele: a double-blind, [further details] (2018) — L-Carnitine

5. Open Questions

• Humic acid complexes: Is there a dose-dependent activation of the Nrf2 pathway in humans, and how stable is the effect over time?
• Bioavailability: Which formulations (e.g., liposomal, complexed) improve the absorption and efficacy of substances such as humic acid complexes or berberine?
• Long-term effects: Do chronic administrations of Nrf2 activators such as sulforaphane or humic acid complexes lead to sustained upregulation of antioxidant enzymes?
• Combination therapies: Are there synergistic effects when combining substances (e.g., humic acid complexes with probiotics or zinc) on antioxidant defence?
• Individual variability: How strongly do genetic polymorphisms in the Nrf2 signalling pathway influence the efficacy of substances such as humic acid complexes or curcumin?
• Clinical endpoints: Can Nrf2 activators such as humic acid complexes measurably influence the progression of chronic diseases (e.g., diabetes, neurodegenerative diseases)?

See also the gap list for all substances. This page is recalculated with each harvest.