Macrophage ACAT1 Aggravates Alcohol‐Associated Liver Disease by Inducing Mitochondrial Damage and NLRP3 Activation

BACKGROUND: Alcohol-associated liver disease (ALD) is a major cause of advanced liver disease, with limited effective clinical interventions, highlighting an urgent need for new therapeutic targets. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key cholesterol-metabolizing acyltransferase that catalyzes the esterification of free cholesterol into cholesteryl esters. It is highly expressed predominantly in macrophages and participates in the regulation of macrophage functions. Nevertheless, its role and underlying mechanism in alcoholic liver injury remain largely unclear. RESULTS: We observed that co-stimulation with ethanol and LPS up-regulated ACAT1 expression, triggered inflammatory responses in macrophages, and aggravated liver function impairment, lipid deposition, and ROS accumulation in mice, thereby contributing to the progression of ALD. Mechanistically, ACAT1 upregulation induces mitochondrial damage and activates the NLRP3 inflammasome. CONCLUSION: ACAT1 is a positive regulatory factor in the inflammatory response of macrophages. It exacerbates ALD by inducing mitochondrial damage and activating NLRP3, providing a theoretical basis for the mechanism by which ACAT1 promotes ALD progression.