Liver Sinusoidal Endothelial Cells in the Regulation of Immune Responses and Fibrosis in MASH Liver Disease

Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role in maintaining liver homeostasis, regulating immune responses, and regulating fibrosis in liver diseases. This review explores the unique functions of LSECs in liver pathology, particularly their roles in immune tolerance, antigen presentation, and the modulation of hepatic stellate cells (HSCs) during fibrosis. LSECs act as key regulators of immune balance in the liver by preventing excessive immune activation while also filtering antigens and interacting with immune cells, including Kupffer cells and T cells. Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of liver disease characterized by steatosis (fatty liver), inflammation, and fibrosis in the liver. It progresses from metabolic dysfunction-associated steatotic liver disease (MASLD), commonly known as non-alcoholic fatty liver disease (NAFLD). MASH is significant because it can lead to advanced liver dysfunction, such as cirrhosis and liver cancer. The prevalence of MASH is increasing globally, particularly in the United States, and is closely linked to rising rates of obesity and type 2 diabetes. Early diagnosis and intervention are vital to prevent severe outcomes, highlighting the importance of studying LSECs in MASH liver disease. However, during chronic liver diseases such as NAFLD, alcoholic liver disease (ALD), and viral hepatitis, LSECs undergo dysfunction, leading to their capillarization, loss of fenestrations, and promotion of pro-fibrotic signaling pathways such as TGF-β. The review also discusses the dynamic interaction between LSECs, HSCs, and other hepatic cells during the progression of liver diseases, emphasizing how changes in LSEC phenotype contribute to liver scarring and fibrosis. Furthermore, it highlights the potential of LSECs as therapeutic targets for modulating immune responses and preventing fibrosis in liver diseases. By restoring LSEC function and targeting pathways associated with their dysfunction, novel therapies could be developed to halt or reverse liver disease progression. The findings of this review reinforce the importance of LSECs in liver pathology and suggest that they hold significant promises as targets for future treatment strategies aimed at addressing chronic liver diseases.