Methylglyoxal in Cancer: Metabolism, Glycation, Context-Dependent Signalling and Therapeutic Implications

Methylglyoxal (MGO) is a reactive α-oxoaldehyde generated principally from glycolytic triose phosphates and controlled by glutathione-dependent glyoxalase activity. Its chemistry permits rapid modification of arginine, lysine and nucleic-acid residues, linking altered carbon metabolism with dicarbonyl stress and cellular signalling. Cancer-associated effects are not uniform. Experimental studies implicate MGO-derived adducts, selected stress-response proteins, epigenetic regulation and extracellular signalling in tumour adaptation; other studies find impaired energy metabolism, growth arrest or cell death following sufficiently intense exposure. This narrative review integrates the chemistry of MGO formation and detoxification with experimental evidence from tumour models, highlights the distinction between within-model biphasic responses and unrelated cross-study dose contrasts, and critically examines the emerging translational literature. Evidence for glyoxalase 1 dependency is compelling in particular molecular contexts but does not establish a universal therapeutic vulnerability. Preclinical findings concerning MGO administration, carbonyl scavenging and glyoxalase modulation also remain difficult to generalise because cell type, exposure kinetics and host toxicity vary. A historical human case series involving 24 patients and a separate 46-patient series are discussed as uncontrolled observations rather than evidence of efficacy. Recent analytical studies of human colorectal tumours support the biological relevance of MGO accumulation but do not establish diagnostic performance. Overall, MGO is best considered a context-sensitive metabolic stressor and source of bioactive molecular modifications; its clinical value depends on stronger quantitative measurements, tumour-selective mechanisms and controlled efficacy and safety evaluation.