Targeting Glyoxalase-1 Pathway with Natural Compounds: A Translational Strategy to Reduce Dicarbonyl Stress and...

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG-Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders.