Dietary context and ethanol-related injury in preclinical models: A contemporary systematic review of predominantly obesogenic diets and liver outcomes.

Diet composition is an important food-derived exposure that may influence alcohol-related tissue injury. However, evidence on how specific dietary contexts modify ethanol-induced injury and its underlying biological mechanisms in controlled preclinical models remains fragmented. This systematic review examined whether defined dietary patterns modify ethanol-related injury in controlled mammalian studies. Following PRISMA 2020, PubMed, Embase, and Scopus were searched for studies published from January 2021 to January 15, 2026. Eligible studies were controlled in vivo mammalian experiments comparing ethanol exposure under defined dietary patterns. Evidence was narratively synthesized by diet type, organ system, and mechanism; random-effects meta-analyses and prespecified interaction analyses were conducted when sufficiently comparable data were available. Twenty-seven studies met the inclusion criteria (24 mouse and three rat studies); 18 used male-only animals, most examined high-fat or Western-type diets, and liver outcomes predominated. Evidence for non-obesogenic diets was limited to one ketogenic-diet study. In acute high-fat-diet models, adding ethanol increased serum ALT (SMD 2.31, 95% CI 1.46-3.16), AST (SMD 1.18, 95% CI 0.54-1.81), and hepatic triglycerides (SMD 2.06, 95% CI 0.96-3.17). Acute interaction analysis identified dietary effect modification only for ALT (MD 74.56, 95% CI 59.03-90.10), while chronic analyses showed a negative interaction for hepatic triglycerides (MD -0.048, 95% CI -0.092 to -0.004; P = 0.03). Extrahepatic, microbiome, and multi-omics findings were sparse and heterogeneous. High-fat and Western-type diets generally exacerbated ethanol-induced hepatic injury, whereas evidence for other dietary patterns remains limited.