From fructose to steatosis, fructose-induced inflammation as a driver of hepatic injury and MAFLD progression: a systematic review of preclinical studies
Marissa Arifin, Wardatul Jannah, Irma Rahayu Latarissa, Neily Zakiyah, Anna Meiliana, Melisa Intan Barliana, Keri LestariBackground
Excessive dietary fructose has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), yet its specific role in driving hepatic inflammation remains incompletely defined. This systematic review aimed to synthesise recent preclinical evidence on the inflammatory and oxidative mechanisms linking fructose-only diets to hepatic injury and MAFLD progression.
Methods
The databases PubMed, Scopus and Web of Science were systematically searched from 2019 to 2024. Eligible studies included preclinical studies that assessed hepatic inflammation and injury following fructose-only diets. Data on inflammatory biomarkers, oxidative stress, histopathology and metabolic parameters were extracted, and the study quality was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies checklist.
Results
14 eligible studies met the inclusion criteria and demonstrated consistent upregulation of pro-inflammatory cytokines (eg, tumour necrosis factor-α, interleukin (IL)-6, IL-1β), activation of nuclear factor kappa-light-chain-enhancer of activated B cells and NOD-like receptor family pyrin domain containing 3 inflammasome pathways and increased oxidative stress markers (eg, malondialdehyde, reactive oxygen species, uric acid). Histological evidence of steatosis, ballooning and inflammation was observed across models, independent of additional dietary stressors. IL-10 was elevated in one study but failed to counteract lipogenesis. Most studies showed moderate to high methodological quality, but the lack of sample size calculations and blinding indicates potential risk of bias and should be considered when interpreting the findings.
Conclusion
This systematic review demonstrates that fructose acts as both a substrate for de novo lipogenesis and an upstream activator of inflammatory signalling, thereby creating a cycle between metabolism and immunity. This mechanistic link explains the progression from simple steatosis to steatohepatitis and fibrosis. Targeting inflammatory pathways while reducing dietary fructose offers a potential strategy for the prevention and therapy of MAFLD.
PROSPERO registration number
CRD420251077702.