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Polyphenol-based modulation of the Glo1–Nrf2–RAGE axis in diabetes and neurodegeneration: mechanistic evidence; translational constraints; and critical appraisal
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DOI：10.3389/fphar.2026.1877182.png)
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Abstract
En 中文
The key pathological mechanisms in diabetes and neurodegeneration generally involve a progressive accumulation of reactive carbonyl species (RCS); accompanied by increased oxidative stress and the accumulation of inflammatory mediators. Thus; a clear understanding of the Glo1–Nrf2–RAGE axis is crucial as it plays a key role in redox imbalance; regulation of cell responses to methylglyoxal (MG)-induced glycation; and chronic inflammation. Even though glyoxalase I (Glo1) detoxifies MG to mitigate advanced glycation end product (AGE) formation; the transcription of antioxidant enzymes by nuclear factor erythroid 2–related factor 2 (Nrf2) is reactivated. Conversely; persistent activation of the receptor for AGE (RAGE) further amplifies inflammatory cascades and tissue damage. A continuous dysregulation of “this axis” can contribute to the pathogenesis of several complications; including diabetes and neurodegeneration. Nevertheless; polyphenols have emerged as nutraceutical candidates that may modulate the Glo1–Nrf2–RAGE axis due to their specialized structural features. Key polyphenols; such as quercetin; resveratrol; curcumin; epigallocatechin gallate; luteolin; and apigenin; enhance Glo1 expression and activity; promote Nrf2 nuclear translocation via Keap1 modification; and lower RAGE expression and ligand binding. However; numerous challenges; such as limited bioavailability; metabolic instability; and “interindividual variability; ” hinder their clinical translation. We have tried to fill the research gap by combining recent evidence from preclinical; clinical; and molecular studies; with the aim of highlighting the pleiotropic effects of these metabolites. In addition; the molecular effects of polyphenolics with reference to modulation of mitochondrial function; regulation of epigenetic mechanisms; and interactions with the gut–brain axis are detailed.
Keywords:
oxidative stress
neurodegeneration
Nrf2
flavonoids
methylglyoxal
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