Activation of Nrf2 by the supplementation of polyphenols in humans: A systematic review and meta-analysis

Background: In animal models, polyphenols have shown an ability to activate nuclear factor erythroid 2-related factor (Nrf2); however, in humans there is no consensus on the effectiveness of this activation. Aim: To analyze the available scientific evidence on the effect of polyphenols on Nrf2 activation in humans. Methods: Inclusion and exclusion criteria: Randomized controlled trials and pre-experimental trials published in English and Spanish. The included studies evaluated Nrf2 activation by polyphenols compared with placebo. A systematic search was carried out in PubMed, Scopus, Web of Science, and Cochrane Library. Results: Nine studies were included. A total of 552 participants (male n  = 376, female n  = 176) were included in the meta-analysis. In a subgroup analysis, polyphenol supplementation did not significantly affect Nrf2 expression; however, in an analysis of each of the polyphenols, isoflavones exhibited the most pronounced upregulation of Nrf2 ( p  < 0.00001), followed by chlorogenic acid and N -methylpyridinium ( p  = 0.0008). Conversely, resveratrol supplementation significantly downregulated Nrf2 activation the activation of Nrf2 ( p  = 0.03). Curcumin, sulforaphane, and bilberry pomace extract showed no statistically significant differences in Nrf2 activation. Summary: The subgroup analysis did not identify statistically significant differences in Nrf2 activation following polyphenol supplementation in humans. Although some compounds, such as isoflavones and chlorogenic acid combined with N -methylpyridinium, showed favorable effects in individual studies, the available evidence is limited due to the small number of studies and their risk of bias. Therefore, methodologically sound clinical trials are needed to confirm these findings.