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

ABSTRACT: 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.

SUBMITTER: Nie Y

PROVIDER: S-EPMC8451456 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStudies have shown that both NOX4 and RhoA play essential roles in fibrosis and that they regulate each other. In lung fibrosis, NOX4/ROS is located upstream of the RhoA/ROCK1 signaling pathway, and the two molecules are oppositely located in renal fibrosis. Currently, no reports have indicated whether the above mechanisms or other regulatory mechanisms exist in liver fibrosis.ObjectivesTo investigate the effects of the NOX4/ROS and RhoA/ROCK1 signaling pathways on hepatic stellate cell (HSC)-T6 cells, the interaction mechanisms of the two pathways, and the impact of UA on the two pathways to elucidate the role of UA in the reduction of hepatic fibrosis and potential mechanisms of HSC-T6 cell proliferation, migration, and activation.MethodsStable cell lines were constructed using the lentiviral transduction technique. Cell proliferation, apoptosis, migration, and invasion were examined using the MTS, TdT-mediated dUTP nick-end labeling, cell scratch, and Transwell invasion assays, respectively. The DCFH-DA method was used to investigate the ROS levels in each group. RT-qPCR and western blotting techniques were utilized to assess the mRNA and protein expression in each group. CoIP and the Biacore protein interaction analysis systems were used to evaluate protein interactions.ResultsThe NOX4/ROS and RhoA/ROCK1 signaling pathways promoted the proliferation, migration, and activation of HSCs. UA inhibited cell proliferation, migration, and activation by inhibiting the activation of the two signaling pathways, but the mechanism of apoptosis was independent of these two pathways. The NOX4/ROS pathway was upstream of and positively regulated the RhoA/ROCK1 pathway in HSCs. No direct interaction between the NOX4 and RhoA proteins was detected.ConclusionThe NOX4/ROS and RhoA/ROCK1 signaling pathways are two critical signaling pathways in a series of behavioral processes in HSCs, and NOX4/ROS regulates RhoA/ROCK1 through an indirect pathway to control the activation of HSCs. Additionally, NOX4/ROS and RhoA/ROCK1 constitute a new target for UA antifibrosis treatment.

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

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