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.

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.

Background: Colorectal cancer (CRC) is the 3rd most common malignancy with the liver being the most common site of metastases. The recurrence rate of colorectal liver metastases (CRLM) after liver resection (LR) is notably high, with an estimated 40% of patients experiencing recurrence within 6 months. In this context, we conducted a meta-analysis to synthesize and evaluate the reliability of evidence pertaining to prognostic factors associated with early recurrence (ER) in CRLM following LR. Methods: Systematic searches were conducted from the inception of databases to July 14, 2023, to identify studies reporting prognostic factors associated with ER. The Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess risk-of-bias for included studies. Meta-analysis was then performed on these prognostic factors, summarized by forest plots. The grading of evidence was based on sample size, heterogeneity, and Egger’s P value. Results: The study included 24 investigations, comprising 12705 individuals, during an accrual period that extended from 2007 to 2023. In the evaluation of risk-of-bias, 22 studies were rated as low/moderate risk, while two studies were excluded because of high risk. Most of the studies used a postoperative interval of 6 months to define ER, with 30.2% (95% confidence interval [CI], 24.1–36.4%) of the patients experiencing ER following LR. 21 studies were pooled for meta-analysis. High-quality evidence showed that poor differentiation of CRC, larger and bilobar-distributed liver metastases, major hepatectomy, positive surgical margins, and postoperative complications were associated with an elevated risk of ER. Additionally, moderate-quality evidence suggested that elevated levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA199), lymph node metastases (LNM) of CRC, and a higher number of liver metastases were risk factors for ER. Conclusion: This review has the potential to enhance the efficacy of surveillance strategies, refine prognostic assessments, and guide judicious treatment decisions for CRLM patients with high risk of ER. Additionally, it is essential to undertake well-designed prospective investigations to examine additional prognostic factors and develop salvage therapeutic approaches for ER of CRLM.

Background: Gallbladder cancer (GBC) is one of the most common biliary cancers and is characterized by its high malignancy. Moreover, the incidence of GBC has been increasing over the decades, partly due to advancements in diagnostic techniques and devices. The purpose of this systematic review is to provide a comprehensive assessment of factors influencing the prognosis of GBC. We aim to identify and evaluate both established and controversial prognostic factors, including lymphocyte-monocyte ratio (LMR), adjuvant therapy, carbohydrate antigen 19-9 (CA199), carcinoembryonic antigen (CEA), tumor mutation status, surgical margins, the presence of gallstones, and jaundice. Methods: We conducted a systematic search of eligible studies in PubMed, Cochrane Library, and Embase. Our analysis focused on data from GBC patients who had undergone surgical resection, with the primary outcome being overall survival. Forest plots were generated using hazard ratios (HRs) to visualize the effect sizes, and the Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess the risk of bias. Results: This study synthesized data from 52 studies, encompassing a total of 23,174 patients over the period of 2000 to 2022. Notably, several factors significantly influenced the outcomes of GBC, including LMR (HR =2.17), CEA (HR =1.81), CA199 (HR =1.56), lymph node stage (HR =2.03), T stage (HR =2.37), presence of invasion (HR =1.74), tumor location (HR =1.42), and surgical margins (HR =2.66). Additionally, chemotherapy (HR =0.75) and radiotherapy (HR =0.56) demonstrated marked improvements in overall survival compared to control arms. Jaundice and the presence of gallstones were not defined as independent predictors, as they reflect advanced stage symptoms in GBC. Conclusions: The findings from this comprehensive review offer valuable insights into the assessment of the necessity for aggressive treatment approaches and the prognostication of GBC patients. Furthermore, there is a need for well-designed, ongoing studies to further advance our understanding of this challenging malignancy.

Background: Multiple risk or protective factors for postoperative pancreatic fistula (POPF) have been suggested in the literature of surgical specialities. We aimed to map existing evidence regarding the risk factors for POPF to help guide future clinical treatment. Methods: We performed an umbrella review by searching the Web of Science, PubMed, Embase, and Cochrane databases until June 19, 2023. Meta-analyses (MAs) that included ≥2 studies were included. Methodological quality was assessed using AMSTAR2 scores and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools were used to quantify the strength of the evidence. Results: Of the 42 MAs, 1 was rated as having high methodological quality, and 4 were rated as moderate. Among the 82 outcomes, 6 were supported by high-quality evidence. Moderate-quality evidence was found for 13 outcomes. The remaining outcomes had either low- or very low-quality evidence. In pancreaticoduodenectomy (PD), protective factors for all-grade POPF include pancreaticogastrostomy (PG) [vs. pancreaticojejunostomy (PJ), moderate quality], external pancreatic ductal stent (vs. no stents, high quality). Risk factors for all-grade POPF in PD include pancreatic duct occlusion (vs. no occlusion, moderate quality) and sealant (vs. no sealant, moderate quality). Polyglycolic acid mesh [vs. no mesh, moderate quality] was a protective factor for clinically relevant POPF (CR-POPF) in PD, omental/falciform ligament wrapping (vs. no wrapping, low quality), and artery-first PD (vs. standard, low quality). In distal pancreatectomy (DP), no factors for all-grade POPF were rated as high- or moderate-quality evidence. Polyglycolic acid mesh (vs. no mesh, moderate quality) was a protective factor for CR-POPF in DP. No factors were rated as high- or moderate-quality evidence in other types of pancreatectomy. In addition, high- and moderate-quality evidence showed that there was little difference in the incidence of pancreatic fistula in PD between minimally invasive and open surgery, duct-to-mucosa and invaginated PJ, Roux-en-Y and conservative reconstruction, extended and standard lymphadenectomy, and in the incidence of pancreatic fistula in DP between fibrin sealant patch and no patch. Conclusions: This umbrella review found varying levels of evidence for the associations between different surgery-related risk factors for POPF. Given the wealth of existing evidence of relatively low quality, future research should focus on improving its credibility.

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.