Liver sinusoidal endothelial cells in liver diseases and hepatocellular carcinoma: molecular mechanisms, physiology, and therapies.

Liver sinusoidal endothelial cells (LSECs) form a specialized discontinuous microvascular interface between sinusoidal blood and the hepatic parenchyma. Functioning as a central regulator of hepatic homeostasis, LSECs integrate metabolic, inflammatory, and hemodynamic signals to maintain sinusoidal permeability, immune tolerance, vascular tone, and lipid exchange. During acute injury or sustained hepatic stress, LSECs may lose their differentiated sinusoidal phenotype and acquire features of capillarization, including fenestrae loss, subendothelial matrix accumulation, impaired scavenging activity, and attenuation of KLF2-eNOS-NO signaling. Capillarized LSECs are not merely a byproduct of hepatic damage; instead, they may function as early endothelial sentinels and important contributors to the amplification of parenchymal injury, inflammation, fibrogenesis, and tumor immune evasion. This review summarizes the physiological functions of LSECs and examines mechanisms through which LSEC dysfunction contributes to acute liver injury, metabolic dysfunction-associated steatotic liver disease, viral hepatitis, cirrhosis, and hepatocellular carcinoma. By comparing conserved mechanisms with disease-specific spatial and molecular triggers, this review highlights how LSEC phenotypic switching disrupts the angiocrine-immune-fibrotic axis and contributes to disease progression. Recent advances in single-cell and spatial omics, LSEC subpopulation heterogeneity, and capillarization-aware therapeutic delivery are further discussed. Finally, therapeutic reprogramming of dysfunctional LSECs toward a quiescent, fenestrated, and tolerogenic phenotype is proposed as a strategy to restore sinusoidal homeostasis and improve treatment of liver diseases.