Fructose Metabolism and Disease Mechanisms: From Nutritional Excess to Obesity and Multiorgan Pathophysiology

Excessive fructose consumption has emerged as a critical driver of obesity and metabolic dysfunction, with far-reaching implications for multiple organ systems. This review synthesizes current evidence on the biochemical and molecular pathways underlying fructose induced disease mechanisms, discussing how fructose metabolism activates the “survival switch”, promotes fat storage, and generates uric acid, mitochondrial dysfunction, and oxidative stress, thereby disrupting energy homeostasis. Key organ-specific consequences are explored, including hepatic steatosis and progression to non-alcoholic fatty liver disease, pancreatic β-cell dysfunction, renal fibrosis, intestinal barrier disruption with microbial dysbiosis, cardiometabolic impairment, pulmonary inflammation, and neurocognitive decline with relevance to Alzheimer’s disease. Moreover, mechanistic insights highlight the role of fructokinase C activation, adenosine triphosphate (ATP) depletion, leptin resistance, pro-inflammatory signaling (mechanistic target of rapamycin complex-1 (mTORC1), renin angiotensin system (RAS), Toll-like receptor 4 (TLR4)), and cross-talk between fructose metabolism and organ-specific pathophysiology. Animal and human studies consistently reinforce the central role of fructose overload in driving obesity and associated complications. Meanwhile, this review frames fructose not merely as a caloric contributor but as a metabolic disruptor, thereby underscoring the urgent need for public health interventions, dietary regulation, and mechanistic research to mitigate fructose-driven metabolic disease.