Rapamycin ameliorates intrahepatic inflammation in MASLD by increasing macrophage fatty acid oxidation levels.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disease and a serious threat to public health. Mammalian target of rapamycin (mTOR) plays an important role in the progression of MASLD and can be a potential therapeutic target. Our data show that rapamycin treatment can alleviate MASLD symptoms, including liver inflammation, steatosis and steatohepatitis, in the WD, CDHFD- or MCD-induced MASLD mouse model, but has no significant effect on hepatic fibrosis. Analysis of the liver immune microenvironment revealed that rapamycin mainly inhibited the inflammatory response of bone marrow-derived macrophages. Moreover, transcriptome sequencing of these macrophages in the livers of MASLD mice treated with or without rapamycin revealed that rapamycin reduced bone marrow-derived macrophage activation and proinflammatory effects. We demonstrated that rapamycin exerts its protective effect mainly by increasing the fatty acid oxidation (FAO) level of macrophages and decreasing their proinflammatory ability during MASLD development, which may provide new ideas for the intervention and treatment of MASLD and MASH.