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

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.