Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis

Activation of the NOX4/NLRP3 inflammasome pathway has been associated with fibrosis in other organs. An imbalance in intestinal bacteria is an important driving factor of liver fibrosis through the liver-gut axis. This study aimed to explore whether the effect of ursolic acid (UA) on liver fibrosis was associated with the NOX4/NLRP3 inflammasome pathways and intestinal bacteria. Wild-type (WT), NLRP3(−/-), and NOX4(−/-) mice and AP-treated mice were injected with CCI4 and treated with or without UA. The intestinal contents of the mice were collected and analyzed by 16S rRNA sequencing. UA alleviated liver fibrosis, which manifested as decreases in collagen deposition, liver injury, and the expression of fibrosis-related factors, and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCI4 injection, liver damage and fibrosis-related factors were significantly decreased in NLRP3(−/-), NOX4(−/-), and AP-treated mice. Importantly, the expression of NLRP3 was obviously inhibited in NOX4(−/-) and AP-treated mice. In addition, the diversity of intestinal bacteria and the abundance of probiotics in NLRP3(−/-) and NOX4(−/-) mice was significantly higher than those in WT mice, while the abundance of harmful bacteria in NLRP3(−/-) and NOX4(−/-) mice was significantly lower than that in WT mice. The NOX4/NLRP3 inflammasome pathway plays a crucial role in liver fibrosis and is closely associated with the beneficial effect of UA. The mechanism by which the NOX4/NLRP3 inflammasome pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.