TLR4 promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis by a mechanism independent of hepatocytes and inflammatory cells

In metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis is the most important prognostic factor, and fibrosis can lead to hepatic cirrhosis and cancer. In the liver toll-like receptor 4 (TLR4) signaling promotes fibrosis. To investigate the role of TLR4 in the development of MASLD, we used a mouse model of MASLD, and we deleted the Tlr4 gene either in the whole body or selectively in inflammatory cells or hepatocytes. Mice with a whole-body deletion of Tlr4 developed MASH with steatosis, hepatocellular injury and inflammation; however, Tlr4 deletion prevented the deposition of fibrosis. Tlr4 deletion on immune cells or in hepatocytes did not prevent fibrosis. These results suggest that activation of TLR4 in other hepatic cells, possibly hepatic stellate cells, or in a combination of cells promotes liver fibrosis in MASLD.