Gene regulatory mechanisms underlying sex- and age-dependent pathophysiology of MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most common chronic liver disease globally, affects nearly one-quarter of adults. Its escalating prevalence is driven by rising rates of obesity associated with sedentary lifestyles, high-caloric Western diets, and population aging. While early-stage MASLD, characterized by simple steatosis, is largely reversible, it can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is marked by inflammation, hepatocyte injury, and fibrosis. MASH poses a risk for the development of cirrhosis and hepatocellular carcinoma. The liver maintains systemic energy homeostasis through dynamic, nutrient-responsive transcriptional programs that regulate gluconeogenesis, lipid storage, fatty acid oxidation, and detoxification; consequently, gene expression profiles change significantly between fed and fasted states to respond to nutritional cues. Sex dimorphism in gene expression markedly shapes MASLD susceptibility and progression, largely mediated by the interplay of sex chromosome-linked genes, hormonal cues, and their downstream regulatory networks. These transcriptional programs drive divergent metabolic and nutrient stress responses that ultimately influence disease trajectory. This review synthesizes current knowledge on sex- and age-dependent transcriptional regulation in liver and its influence on development of MASLD, integrating findings from animal models, human studies, and multi-omics datasets. Ultimately, understanding how these gene expression differences shape lipid metabolism, inflammation, fibrogenesis, and nutrient-stress responses is essential for developing more precise and effective therapeutic strategies.