Biological Sex Modifies the Link Between Nutrient Intake and MASLD: Intrinsic Oxidative Vulnerability in Females

Abstract Purpose Whether biological sex modifies the association between diet and liver disease remains unclear. We applied a reverse-translational strategy linking sex-stratified population data with mechanistic studies in a murine model. Methods We analyzed associations between dietary nutrients and hepatic steatosis in a community-based Japanese cohort (the Shika study). Based on the human findings, mice were fed a Western diet with fructose–sucrose–supplemented water to investigate sex-dependent mechanisms. Results In the Shika study, steatosis in women—but not in men—was associated with higher dietary cholesterol/fat density and with a higher sucrose-to-total carbohydrate ratio. Modeling this risk in mice revealed a dissociation between systemic metabolism and liver pathology: despite exhibiting milder systemic obesity than males, females developed more pronounced fibrosis and oxidative injury. Transcriptomic analysis identified distinct sex-biased pathways. Males preferentially upregulated genes involved in glutathione metabolism (e.g., Gst, Gpx). In contrast, females exhibited higher expression of genes associated with microsomal ω-oxidation and acyl-CoA hydrolysis (e.g., Cyp4a, Acot), accompanied by marked oxidative stress and a Kupffer cell–skewed inflammatory signature. Conclusions By integrating sex-stratified epidemiological evidence in humans with the intrinsic oxidative vulnerability identified in mice, our findings highlight biological sex as a critical modifier of nutrition-driven liver injury. These findings suggest that rigorous nutritional management is particularly important for preventing disease progression in women with metabolic dysfunction-associated steatotic liver disease (MASLD).