Sex dimorphism in gene expression, mediated by sex chromosome-linked genes, hormonal cues, and their downstream regulatory networks, markedly shapes MASLD susceptibility and progression through divergent transcriptional programs governing lipid metabolism, inflammation, fibrogenesis, and nutrient-stress responses.
MASLD affects nearly one-quarter of adults globally and is the most common chronic liver disease worldwide.
Sex dimorphism in gene expression markedly shapes MASLD susceptibility and progression.
The liver maintains systemic energy homeostasis through dynamic, nutrient-responsive transcriptional programs.
Age-dependent transcriptional regulation in the liver influences MASLD development alongside sex-dependent mechanisms.
Understanding sex- and age-dependent gene expression differences is identified as essential for developing more precise and effective therapeutic strategies for MASLD.
This research suggests that the most common chronic liver disease in the world — a condition called metabolic dysfunction-associated steatotic liver disease (MASLD) — affects about one in four adults and is becoming more prevalent due to obesity, poor diets, lack of exercise, and aging populations. The disease can progress from a relatively mild state of fat accumulation in the liver to a more serious condition involving inflammation and scarring, which can eventually lead to liver failure or cancer. A key insight from this review is that men and women develop and experience this disease differently, and that these differences are deeply rooted in how genes are regulated differently between the sexes. This research suggests that the biological differences between males and females — including differences in sex chromosomes, hormones like estrogen and testosterone, and the molecular networks these hormones control — lead to distinctly different patterns of gene activity in the liver. These differences affect how the liver handles fat storage, inflammation, scarring, and responses to nutritional stress such as fasting or overeating. Age also plays an important role, with gene activity in the liver changing over time in ways that can increase disease risk. The review draws on studies in animals, humans, and large-scale genetic and molecular datasets to build a comprehensive picture of these regulatory mechanisms. This research suggests that recognizing and accounting for sex- and age-based differences in liver gene regulation could be critical for developing better, more targeted treatments for MASLD. Currently, many therapies do not distinguish between male and female patients or account for age-related changes, which may limit their effectiveness. A deeper understanding of why men and women differ in their disease risk and progression could open the door to more personalized medical approaches for this increasingly common and serious condition.
Morral N. (2026). Gene regulatory mechanisms underlying sex- and age-dependent pathophysiology of MASLD.. Clinical science (London, England : 1979). https://doi.org/10.1042/CS20250052