Liver sinusoidal endothelial TGF-β signaling accelerates partial endothelial–mesenchymal transition and MASH through Notch

BACKGROUND & AIMS: As the global prevalence of obesity continues to rise, metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a significant burden on healthcare systems worldwide. Liver sinusoidal endothelial cells (LSECs) are recognized as crucial regulators of hepatic homeostasis. However, their role in the progression of MASH remains poorly understood, particularly given their early capillarization during disease onset. In this study, we sought to investigate the specific role of LSECs in MASH progression and the underlying molecular mechanisms driving their dysfunction. METHODS: We analyzed single-cell RNA sequencing of the liver from advanced MASH mice (from 6 mice/condition) and conducted in vivo experiments using various LSEC-specific transgenic mouse models (n = 3-10 mice/condition). Primary LSECs (n = 3-6 mice/condition) and human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments. RESULTS: Using single-cell RNA sequencing data from MASH-affected livers, we identified a unique population of biphenotypic cells co-expressing markers of both LSECs and mesenchymal cells. Through lineage tracing in LSEC-specific reporter mice, we demonstrated that these biphenotypic cells arose from LSECs undergoing partial endothelial-mesenchymal transition (EndMT) in MASH (p