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.

Pyroptosis has an important role in liver inflammation and fibrosis. The role of KC pyroptosis in liver fibrosis was unclear. Ursolic acid (UA) has antifibrotic effects, but study on the effect and mechanism of UA on KC pyroptosis in liver fibrosis has not been reported. Therefore, we induced KC pyroptosis using Lipopolysaccharide (LPS) and nigericin (Nig) in vitro. C57BL/6J mice were intraperitoneally injected with carbon tetrachloride (CCl₄) to establish a liver fibrosis model. We demonstrated that UA attenuated CCl₄-induced liver fibrosis, liver damage, and KC pyroptosis of liver tissue. Moreover, KCs were treated with UA and small interfering RNA of NOX2, which showed that inhibiting the NOX2/NLRP3 inflammasome signaling pathway attenuated KC pyroptosis and UA abrogated this effect via suppressing this pathway in vitro. Furthermore, mice were treated with UA, GSK2795039 (a specific inhibitor of NOX2) or MCC950 (a specific inhibitor of NLRP3). Compared with inhibiting NOX2 alone, inhibiting NOX2 in the presence of UA did not markedly ameliorate KC pyroptosis of liver tissue in CCl₄-induced liver fibrosis. In addition, when NLRP3 was silenced or inhibited, the result was similar to that of knocking down NOX2 in vivo and in vitro. These results indicate that UA attenuates liver fibrosis in mice via inhibiting KC pyroptosis, which may be through the suppression of NOX2/NLRP3 inflammasome signaling pathway. It may be a new target for treating liver fibrosis and provide a new theoretical basis for the use of UA to treat liver fibrosis.

Background. Variceal rebleeding is a significant and potentially life-threatening complication of cirrhosis. Unfortunately, currently, there is no reliable method for stratifying high-risk patients. Liver stiffness measurements (LSM) have been shown to have a predictive value in identifying complications associated with portal hypertension, including first-time bleeding. However, there is a lack of evidence to confirm that LSM is reliable in predicting variceal rebleeding. The objective of our study was to evaluate the ability of generating a extreme gradient boosting (XGBoost) algorithm model to improve the prediction of variceal rebleeding. Methods. This retrospective analysis examined a cohort of 284 patients with hepatitis B-related cirrhosis. XGBoost models were developed using laboratory data, LSM, and imaging data to predict the risk of rebleeding in the patients. In addition, we compared the XGBoost models with traditional logistic regression (LR) models. We evaluated and compared the two models using the area under the receiver operating characteristic curve (AUROC) and other model performance parameters. Lastly, we validated the models using nomograms and decision curve analysis (DCA). Results. During a median follow-up of 66.6weeks, 72 patients experienced rebleeding, including 21 (7.39) and 61 (21.48) patients who rebleed within 6weeks and 1year, respectively. In brief, the AUC of the LR models in predicting rebleeding at 6weeks and 1year was 0.828 (0.7590.897) and 0.799 (0.7380.860), respectively. In contrast, the accuracy of the XGBoost model in predicting rebleeding at 6weeks and 1year was 0.985 (0.9070.731) and 0.931 (0.8060.935), respectively. LSM and high-density lipoprotein (HDL) levels differed significantly between the rebleeding and nonrebleeding groups, with LSM being a reliable predictor in those models. The XGBoost models outperformed the LR models in predicting rebleeding within 6weeks and 1year, as demonstrated by the ROC and DCA curves. Conclusion. The XGBoost algorithm model can achieve higher accuracy than the LR model in predicting rebleeding, making it a clinically beneficial tool. This implies that the XGBoost model is better suited for predicting the risk of esophageal variceal rebleeding in patients.

Background. Cirrhosis esophageal variceal rebleeding is a major complication of chronic cirrhosis. The hepatic venous pressure gradient (HVPG) can predict the risk of rebleeding in patients with cirrhosis and has a good correlation with liver stiffness measurement (LSM). However, there are currently few studies based on liver stiffness to predict the risk of rebleeding in patients with liver cirrhosis. This study is aimed at exploring whether liver stiffness can predict rebleeding in patients with hepatitis B virus-related cirrhosis and developing an easy-to-use nomogram for predicting the risk of rebleeding in patients with liver cirrhosis undergoing secondary prevention. Methods. A prospective analysis of 289 cirrhosis patients was performed. Univariate and multivariate analyses were used to identify independent prognostic factors to create a nomogram. The performance of the nomogram was evaluated by using a bootstrapped-concordance index and calibration plots. Results. Use of a nonselective beta-blocker (NSBB) drug, LSM, hemoglobin, and platelet count were identified as factors that could predict rebleeding. We created a nomogram for rebleeding in cirrhosis by using these risk factors. The predictive ability of the nomogram was assessed by the -index (0.772, 95% CI 0.732–0.822). The results of the calibration plots showed that the actual observation and prediction values obtained by the nomogram had good consistency. Conclusions. LSM can predict the risk of rebleeding in patients with cirrhosis, while the nomogram is a conventional tool for doctors to facilitate a personalized prognostic evaluation.

IntroductionActivation 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 bacteriaMethodsWild-type (WT), NLRP3^−/−, and NOX4^−/− mice and AP-treated mice were injected with CCL4 and treated with or without UA.ResultUA alleviated liver fibrosis and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCL4 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.ConclusionThe 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 pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.