Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet

Despite the importance of metabolic dysfunction-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high-fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single-nucleus RNA sequencing of livers revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female <i>vs.</i> male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female <i>vs.</i> male patients with MASH. These results highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.