Fructose, Advanced Glycation, And Metabolic Dysfunction: Molecular Pathways Linking Oxidative Stress, Inflammation, And Masld

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder closely associated with obesity, type 2 diabetes, dyslipidemia, and cardiovascular complications. Excessive fructose consumption may contribute to MASLD development and progression by promoting hepatic de novo lipogenesis, advanced glycation end product (AGE) formation, oxidative stress, and chronic inflammation. This review aims to critically examine the molecular pathways linking fructose metabolism and AGE–RAGE signaling to hepatic injury and cardiovascular dysfunction, highlighting their interconnected roles within the liver–heart axis. Fructose metabolism increases the availability of lipogenic substrates and reactive carbonyl intermediates, favoring lipid accumulation and AGE generation. Subsequent activation of the receptor for AGEs (RAGE) stimulates oxidative and inflammatory signaling, including reactive oxygen species production and NF-κB activation. These processes may impair antioxidant defenses, promote mitochondrial dysfunction, activate hepatic stellate cells, and contribute to steatohepatitis and fibrosis. Beyond the liver, AGE–RAGE signaling is implicated in endothelial dysfunction, vascular inflammation, atherosclerosis, and adverse cardiac remodeling. Intestinal barrier disruption and inflammatory mediator release may further amplify these interconnected metabolic disturbances. We also discuss experimental and clinical evidence concerning fructose intake, hepatic and cardiovascular outcomes, and emerging therapeutic approaches targeting glycation, oxidative stress, and inflammation. However, heterogeneity in dietary exposures, study designs, and clinical endpoints limits causal interpretation. By integrating metabolic, inflammatory, and vascular mechanisms, this review identifies potential therapeutic targets and research priorities for understanding and mitigating fructose-associated cardiometabolic injury in MASLD. Particular attention is given to the distinction between mechanistic findings and human evidence, as well as the need for larger studies.