Fructose as a systemic metabolic signal orchestrating metabolic dysfunction-associated steatotic liver disease pathogenesis

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30% of the global population, yet the specific role of dietary fructose in disease progression remains inadequately defined. This review delineates the “Fructose-ectopic lipid accumulation (ELA)-MASLD” axis, identifying refined fructose (e.g., from sugar-sweetened beverages) not merely as a substrate but as a systemic signal that coordinates a pathological metabolic network. Hepatic fructose metabolism via the ketohexokinase-C (KHK-C) pathway bypasses the rate-limiting phosphofructokinase-1 (PFK-1) checkpoint, promotes unregulated de novo lipogenesis (DNL), ATP depletion, and organellar stress. We identify the functional decline of subcutaneous adipose tissue (SAT) plasticity as an important driver of this lipotoxic cascade. This tends to result in systemic lipid spillover, promoting an inflammatory cascade that impairs the intestinal barrier and induces insulin resistance (IR) in skeletal muscle and bystander organs. Furthermore, we discuss how genetic variants amplify this toxicity and critically evaluate emerging preclinical hypotheses regarding epigenetic remodeling and transgenerational inheritance. Finally, we propose stratified management strategies that integrate evidence-based nutritional modifications with targeted pharmacotherapy, distinguishing between hepatic-dominant and adipose-derived lipid excess to optimize clinical outcomes.