The role of liver sinusoidal endothelial cells in metabolic dysfunction-associated steatotic liver diseases and liver cancer: mechanisms and potential therapies

Abstract

Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.