Ursolic acid ameliorates metabolic dysfunction-associated fatty liver disease by regulating the NOX4/ROS/NLRP3 pathway

Ursolic acid (UA) is a monomeric traditional Chinese medicine with unique anti-inflammatory properties. Metabolic fatty liver (MAFL)/metabolic steatohepatitis (MASH) is an early/progressive stage of metabolic dysfunction-associated fatty liver disease (MAFLD). Whether UA affects the progression of MAFLD and whether it is related to the ROS/TXNIP/NLRP3 pathway have not been reported. Wild-type (WT), NLRP3 −/− , and NOX4 −/− mice and Apocynin (AP)-treated mice were fed a low-fat or high-fat diet for 24 weeks and treated with or without UA for 6 weeks. ELISA and histological analysis were used to assess liver injury and lipid deposition. RT–qPCR, Western blotting and immunofluorescence were conducted to measure the mRNA and protein expression of factors related to inflammation, lipid metabolism, liver fibrosis and NOX4/ROS/NLRP3. UA treatment attenuated HFD-induced lipid deposition, inflammation and fibrosis. This was demonstrated by decreases in weight, liver enzymes, triglycerides, lipid deposition, and the expression of proinflammatory factors (TNF-a, IL-1β, IL-6), lipid metabolism-related factors (FAS, SREBP1, ACC1), and liver fibrosis-related factors (α-SMA, collagen-1, TIMP-1) and an improvement in glucose tolerance and insulin tolerance. The levels of NOX4, ROS, and NLRP3 were significantly inhibited by UA treatment in HFD-fed mice, and the progression of MAFLD was also significantly decreased in NLRP3 −/− , NOX4 −/− , and AP-treated mice without UA treatment. Moreover, the expression of NLRP3 was significantly inhibited in NOX4 −/− and AP-treated mice. UA may attenuate MAFLD-related lipid deposition, liver inflammation and fibrosis in vivo through the NOX4/ROS/NLRP3 pathway. UA treatment may provide a new approach for NASH therapy in humans.