Fructose and Alcohol Hepatotoxicity: Demographic Overlap and Mechanistic Interactions

As metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) grow increasingly prevalent, it is essential to improve understanding of the contributing factors and how these conditions may interact. Metabolic and alcohol-related liver injury frequently co-occur, prompting the introduction of the term metabolic dysfunction and alcohol-associated liver disease (MetALD) to describe individuals with MASLD who also consume significant amounts of alcohol. Among the exposures relevant to MetALD, dietary fructose is of particular interest because it shares multiple mechanisms of hepatotoxicity with alcohol. This review synthesizes current evidence for hepatotoxic interactions, emphasizing areas most relevant to MetALD pathogenesis. Epidemiologic data indicate substantial overlap between populations with high fructose and alcohol exposure, while clinical studies increasingly associate combined exposure with greater fibrosis progression and adverse liver outcomes. Several mechanistic pathways have been shown to overlap in terms of their interactions with fructose and ethanol, including endogenous fructose generation, cytochrome P450 2E1 (CYP2E1) induction, mitochondrial dysfunction, dysregulated lipid metabolism, uric acid-driven inflammasome signaling, and disruption of the gut–liver axis. Emerging evidence suggests that these pathways interact in ways that may amplify injury beyond the effects of either exposure alone. Greater integration of the alcohol and metabolic liver disease fields will be necessary to clarify mechanistic interactions, determine risk factors, and develop effective interventions for this increasingly common form of liver injury.