Metabolic reprogramming and epigenetic effects due to reducing sugars and glycation products in cancer.

Cancer cells have the ability to reprogram their metabolism to meet the proliferative and survival demands. These metabolic alterations involve the formation of many active metabolites associated with epigenetic modifications or remodelling together driving tumourigenesis through self-perpetuating feedback loops. Among the various metabolic stressors, reducing sugars, principally glucose and fructose, lactate, acetyl-CoA, glycolytic intermediates such as 3-deoxyglucosone, glyoxal, polyol pathway metabolites, and methylglyoxal effectively modulate the chromatin remodelling and gene expression. These processes lead to dysregulated DNA methylation and histone modifications involving acetylation, methylation, polysialylation, lactylation, and glycation establishing a tumourigenic environment. Elevated levels of reducing sugars and glycolytic intermediates also contribute to the formation of a large group of reactive molecules termed advanced glycation intermediates (AGIs) and advanced glycation end products (AGEs), which interact with their receptor RAGE to activate signalling cascades resulting in oxidative stress, inflammation, and aberrant gene regulation. Furthermore, the AGE-RAGE axis reprograms cancer metabolism influencing key signalling pathways including PI3K/AKT/mTOR and NF-κB. The epigenetic alterations and metabolic perturbations induced by reducing sugars and non-enzymatic glycation reactions also influence the tumour microenvironment (TME) through extracellular matrix (ECM) remodeling, angiogenesis, and immune evasion. This review elucidates the crosstalk between metabolic reprogramming, AGE-RAGE-mediated signalling, and epigenetic modulation that forms a complex network associated with cancer initiation, progression, and resistance to therapy. Understanding the molecular interplay between these pathways could pave the way for novel metabolic and epigenetic therapeutic strategies aimed at disrupting this vicious cycle and impeding tumour growth.