Sex-stratified adipose-liver circuits in human MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common, clinically heterogeneous condition associated with liver-related and cardiometabolic morbidity. Sex differences in MASLD prevalence and progression are well recognized, but how they extend across the liver and visceral adipose tissue (VAT), a major source of lipid and endocrine signals to the liver, remains unclear. Here, we profiled paired liver and VAT biopsies from women and men with and without MASLD, generating single-nucleus datasets of 34 liver samples and 40 VAT samples, including 32 patient-matched pairs. In liver, women with MASLD showed a higher Kupffer-cell triglyceride-catabolism score (1.30-SD female-male difference; FDR=0.0022), accompanied by directionally consistent hepatocyte and endothelial programs. In VAT, women with MASLD showed higher adipocyte lipid and oxidative metabolism (0.87-1.15 SD; FDR<0.05 across seven pathways) together with macrophage immune activation, whereas men with MASLD showed stronger stromal communication routes. Across matched patients, gene modules linked VAT adipocyte and macrophage states to liver hepatocyte stress and lipid-receipt states. Bulk RNA-seq module scoring and paired liver-VAT analyses in 293 patients supported hepatic stress in both sexes, lower adipocyte signaling in women with increasing steatosis, and cross-tissue adipocyte-hepatocyte coupling (r=0.30; FDR=2.1e-6). Together, these findings identify distinct sex-associated transcriptional states in liver and VAT in MASLD and show that these states are coordinated across both tissues within the same individuals.