The activation of stimulator of interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown. STING and NLRP3 inflammasome signaling pathways are activated in fibrotic livers but are suppressed by Sting knockout. Sting knockout ameliorated hepatic pyroptosis, inflammation, and fibrosis. In vitro, STING induces pyroptosis in primary murine hepatocytes by activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) are identified to regulate NLRP3 expression in STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhances interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promotes STING-induced Nlrp3 transcription in hepatocytes. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gasdermin D (Gsdmd) knockout attenuate hepatic pyroptosis, inflammation, and fibrosis. RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes show that oxidative stress and metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. The STING-NLRP3-GSDMD axis inhibition suppresses hepatic ROS generation. In conclusion, this study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence worldwide, but there are no medications approved for treatment. Gut microbiota would be a novel and promising therapeutic target based on the concept of the gut–liver axis in liver disease. We reviewed randomized controlled trials on gut microbiota therapy in NAFLD in this study to evaluate its efficacy and plausibility in NAFLD.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 ⁺ LSECs promote the recruitment of CD63 ⁺ monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

Objective: Transjugular intrahepatic portosystemic shunt (TIPS) is a high-bleeding-risk vascular intervention. The association between TIPS-related hemorrhage and preprocedural platelet (PLT) count remains unclear. Methods: This was a retrospective cohort study including patients receiving TIPS procedures for complications related to portal hypertension due to liver cirrhosis between 2011 and 2022. Logistic regression and subgroup analyses were performed to evaluate the relationship between TIPS-related hemorrhage and preprocedural PLT count. Patients were divided into two groups based on a PLT threshold of 50 × 10 ⁹ /L. Furthermore, patients with PLT count < 50 × 10 ⁹ /L were stratified into two subgroups based on a threshold of 20 × 10 ⁹ /L. The primary endpoint was TIPS procedure-related hemorrhage. Results: A total of 632 patients with liver cirrhosis who underwent TIPS were categorized into two groups based on their PLT counts of 50 × 10 ⁹ /L. The incidence of TIPS-related hemorrhage was 2.8% in the PLT < 50 × 10 ⁹ /L group ( n = 417) and 1.9% in the PLT ≥ 50 × 10 ⁹ /L group ( n = 215) (95% CI: 0.23–1.97; P = 0.480). In subgroup analysis, the bleeding rate was 0% in PLT < 20 × 10 ⁹ /L group ( n = 10) and 2.9% in PLT 20–50 × 10 ⁹ /L group ( n = 205). No statistically significant intergroup differences in bleeding rates were found (95% CI: 0–9.7; P = 0.501). In the univariate and multivariate analysis, advanced age is the independent risk factor for TIPS-related bleeding (OR = 1.054, 95% CI: 1.006–1.105, P = 0.028). Conclusion: This study revealed that preoperative PLT count is not associated with TIPS procedure-related hemorrhage in patients with cirrhosis. Patient age should be carefully considered in the preoperative assessment.