Liver sinusoidal endothelial cells in hepatic fibrosis: opportunities for future strategies

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the interface between the hepatic vasculature and parenchymal cells, playing a crucial role in maintaining hepatic homeostasis. Under pathological conditions, LSECs undergo capillarization, marked by the loss of fenestrae and formation of a basement membrane, thereby impairing microcirculation and promoting fibrosis. Beyond capillarization, LSECs experience a spectrum of pathological changes-including angiogenesis, endothelial-to-mesenchymal transition (EndMT), autophagy, and senescence-all of which contribute to fibrogenesis through distinct molecular pathways. Moreover, LSECs orchestrate liver fibrotic remodeling through dynamic crosstalk with hepatic stellate cells (HSCs), hepatocytes, Kupffer cells, and immune cells, exerting both pro- and anti-fibrotic effects. This review comprehensively summarizes LSECs dysfunction in hepatic fibrosis, with a particular focus on intercellular communication and emerging therapeutic strategies. Elucidating the regulatory networks that govern LSECs behavior may uncover new opportunities for the diagnosis and treatment of chronic liver disease.