X-chromosome gene dosage shapes MASLD beyond sex hormones.

Metabolic dysfunction-associated steatotic liver disease (MASLD) shows substantial sex-related differences, often attributed to sex hormones. However, this purely hormone-centric view may be oversimplistic. Studies comparing Turner syndrome (TS, 45X) and Klinefelter syndrome (KS, 47XXY) to euploid controls indicate that variations in X-chromosome dosage are closely associated with cardiometabolic burden and increased MASLD risk, even before puberty and irrespective of sex hormone levels. Transcriptomic studies further reveal genome-wide, dosage-sensitive regulatory effects of X-chromosome quantity. This opinion article argues that X-chromosome dosage is an active biological variable capable of reprogramming cardiometabolic and hepatic pathways. By highlighting TS and KS as models of liver disease, we suggest a framework to stimulate further research and improve our understanding of sex-specific heterogeneity in MASLD.