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Background: Nonalcoholic fatty liver disease (NAFLD) has developed as a leading public wellness challenge as a result of changes in dietary patterns. Unfortunately, there is still a lack of effective pharmacotherapy methods for NAFLD. Wang's empirical formula (WSF) has demonstrated considerable clinical efficacy in treating metabolic disorders for years. Nevertheless, the protective effect of WSF against NAFLD and its underlying mechanism remains poorly understood. Methods: The NAFLD model was established using a 17-week high-sucrose and high-fat (HSHF) diet with 32 ICR mice. In assessing the therapeutic efficacy of WSF on NAFLD, we detected changes in body weight, viscera weight, biomarkers of glycolipid metabolism in serum and liver, transaminase levels and histopathology of liver with H&E and Oil Red O staining after oral administration. The chemical components in WSF were extensively identified and gathered utilizing the HPLC-Q-TOF/MS system, database mining from HMDB, MassBank, and TCMSP databases, alongside literature searches from CNKI, Wanfang and VIP databases. The forecast of network pharmacology approach was then utilized to investigate the probable mechanisms by which WSF improves NAFLD based on the performance of prospective target identification and pathway enrichment analysis. Besides, molecular docking was also conducted for the verification of combination activities between active components of WSF and core proteins related to NAFLD. In final, validation experiments of obtained pathways were conducted through ELISA, immunohistochemistry (IHC), and western blot (WB) analysis. Results: Pharmacodynamic outcomes indicated that WSF intervention effectively mitigated obesity, fat accumulation in organs, lipid metabolism disorders, abnormal transaminase levels and liver pathology injury in NAFLD mice (P < 0.05, 0.01). A total of 72 existent ingredients of WSF were acquired by HPLC-Q-TOF/MS and database, and 254 common targets (11.6% in total targets) of NAFLD and WSF were identified. Network pharmacology revealed that WSF presses NAFLD via modulating TNF, IL6, AKT1, IL1B, PTGS2 (COX2), and other targets, and the probable pathways were primarily inflammatory signaling pathways, as confirmed by molecular docking. Molecular biology experiments further conformed that WSF could decrease levels of inflammatory factors like IL-1β, IL-6 and TNF-α (P < 0.01) and expression of TLR4, NF-κB and COX-2 (P < 0.05, 0.01) in the liver. Conclusion: WSF treatment effectively protects against lipid metabolism disorders and liver inflammation injury in HSHF diet-induced NAFLD mice, and its molecular mechanism might be via suppressing the TLR4/NF-κB/COX-2 inflammatory pathway to reduce the release of inflammatory cytokines in the liver. [ABSTRACT FROM AUTHOR]

Introduction: Mitochondrial membrane potential (MMP) and mitochondrial mass (MM) affect mitochondrial function and lymphocyte activation, but few studies on HBV infection exist. This study aimed to investigate the regulatory mechanism of mitochondrial dysfunction during HBV infection and its clinical significance by analyzing the alterations of MM and MMPlow in peripheral blood immune cells. Methods: The study enrolled 90 participants, including healthy volunteers(HC) and patients with HBV infection, HBV patients were divided into chronic hepatitis B patients (CHB) and liver cirrhosis (LC) according to the study, and CHB was also divided into an inflammation group and a non-inflammation group. Flow cytometry was used to analyze the changes of MM and MMPlow in peripheral blood immune cells. These analyses were correlated with the presence of CHB and LC and indexes related to liver inflammation. Results: The study revealed significant variations in the percentage of MMPlow and MM of CD8+T cells associated with the progression of the disease. The MMPlow percentage of CD8+T cells in the LC group exhibited a notable decrease compared to the HC group and CHB groups. Moreover, MMPlow of CD8+T cells demonstrated potential in distinguishing CHB and LC (AUC=0.7341, P=0.0032). Furthermore, in exploring the link between mitochondrial function of immune cells and liver inflammation, the study found a negative correlation between the MMPlow ratio of CD4+T and CD8+T cells and AST (p=0.0039 and P=0.0070, r=-0.4405 and r=-0.4146), while the MM of CD8+T cells displayed a positive correlation with AST (p=0.0013, r=0.4865). In CHB patients with normal ALT but liver inflammation detected on B-scan ultrasonography, a significant decrease was observed in the MMPlow percentage of CD8+T (66.13 ± 14.27), CD56+NK(57.77 ± 17.40) and CD4-CD8-T (61.98 ± 15.98) cells. Furthermore, it was also found that the percentage of MMPlow in CD4-CD8-T cells could serve as an indicator for early liver inflammation and injury (AUC=0.8408, P=0.0052). Discussion: In this study, we conducted a systematic analysis of the percentage of lymphocyte MMPlow and MM in various stages of HBV infection. Our findings revealed a correlation between MMPlow and MM and early liver inflammation, as well as the progression of the infection. This study marked the first demonstration of the clinical diagnostic value of MMPlow and MM in HBV infection. Furthermore, this was the first study to discuss the mitochondria of lymphocytes and liver inflammation in HBV infection. It enhanced the understanding of the role of T cells in liver inflammation, and elucidated potential markers for the early detection of liver injury and clinical cirrhosis. [ABSTRACT FROM AUTHOR]

Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver leads to long-term alterations to the liver macrophage compartment. We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single-cell CITE-sequencing, single-nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection. We show that T. brucei brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection. Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term. Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches. [Display omitted] • Trypanosoma infection elicits hepatic infiltration of monocyte-derived macrophages. • A cured infection leaves a long-term transcriptomic and epigenomic imprint on Kupffer cells, altering some of their functions. • Kupffer cell imprinting may be at least partly mediated by their niche cells, which also display long-term alterations upon cure. • Cured animals are significantly better protected against a secondary bacterial infection. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the anti-inflammatory effect of black cumin seed oil (BCSO) and its nanoemulsion on lipopolysaccharide (LPS)-induced liver injury in mice. Methods: LPS-induced acute liver injury mouse model was used to evaluate the effects of BCSO and its nanoemulsion formulation on liver function. Hepatic inflammatory markers including Toll-like receptor 4 (TLR4), interleukin(IL)-1β, heme-oxygenase 1, BAX, and BCL-2 were assessed using real-time PCR. Additionally, protein levels of reduced glutathione, tumor necrosis factor-α, and IL-6 were measured using ELISA, and histological analysis was performed. Indomethacin was used as a standard positive control for comparison. Results: BCSO reduced LPS-induced liver injury and exhibited strong anti-inflammatory effects by downregulating the expression of TLR4, IL-1β, IL-6, tumor necrosis factor-α, and heme-oxygenase 1. Additionally, BCSO demonstrated antioxidant properties by increasing reduced glutathione protein levels and decreasing key apoptotic markers BAX and BCL-2 in hepatocytes. The nanoemulsion formulation further enhanced these anti-inflammatory, antioxidant, and anti-apoptotic effects, and histological examination confirmed this effect. Combining BCSO with indomethacin at a lower dose improved efficacy, thereby reducing its potential side effects. Conclusions: The investigation reveals the anti-inflammatory impact of BCSO and its nanoemulsion formulation on LPS-induced liver oxidative stress, inflammation, and apoptosis. [ABSTRACT FROM AUTHOR]

Background: Hepatic macrophages play an indispensable role in liver pathophysiology, serving as key orchestrators of both liver injury and repair processes. ATG16L1 (autophagy‐related 16 like 1) has emerged as a novel and critical autophagy marker. In macrophages, ATG16L1 assumes a particularly crucial role. The current understanding of how macrophage ATG16L1 regulates liver inflammation in the context of liver fibrosis is unclear. Methods: This study included clinical patient samples of liver fibrosis and established a murine model with myeloid‐specific Atg16l1 knockout, creating a mouse model of liver fibrosis. Employing RNA sequencing, we sought to elucidate the mechanisms of macrophage ATG16L1 in liver fibrosis by identifying critical signaling pathways. To assess the influence of macrophage ATG16L1 on hepatocyte apoptosis and hepatic stellate cell (HSC) activation, we constructed a dedicated culture system. Ultimately, the introduction of mice with myeloid‐specific Atg16l1 knock‐in substantiated the protective role of myeloid‐specific Atg16l1 against inflammatory signaling, hepatocyte apoptosis, and activation of HSCs. Results: An upregulation of the ATG16L1 signal was observed in the liver tissues of patients with liver fibrosis and in fibrotic mice, predominantly localized to hepatic macrophages. In Atg16l1ΔMφ mice afflicted with liver fibrosis, we detected exacerbated liver damage, evidenced by heightened inflammatory signal expression, increased hepatocyte apoptosis, and enhanced activation of HSCs. The absence of macrophage Atg16l1 was found to result in elevated TNF receptor‐associated factor 1 (TRAF1) signaling, triggering inflammatory activation, intensifying hepatocyte apoptosis, and facilitating HSC activation through the transforming growth factor beta 1 (TGF‐β1) signaling. The detrimental effects of macrophage Atg16l1 depletion were demonstrated to be mitigated upon Atg16l1 reintroduction. Conclusions: This research delved into the mechanisms by which the macrophage ATG16L1 signal influences inflammatory signaling, hepatocyte apoptosis, and activation of HSCs in liver fibrosis. Consequently, it offers theoretical substantiation and an experimental groundwork for the identification of biological targets for therapeutic intervention in liver fibrosis. [ABSTRACT FROM AUTHOR]

Gaudichaudione H (GH) is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae). Being an uncommon rare caged polyprenylated xanthone, the potential pharmacological functions of GH remain to be fully elucidated currently. In this study, we primarily focused on identifying potential bioavailable targets and elucidating related therapeutic actions. Herein, the network pharmacology analysis, metabolomics analysis and genome-wide mRNA transcription assay were performed firstly to predict the major pharmacological action and potential targets of GH. To confirm the hypothesis, gene knockout model was created using CRISPR/Cas9 method. The pharmacological action of GH was evaluated in vitro and in vivo. Firstly, our results of network pharmacology analysis and omics assay indicated that GH significantly activated NRF2 signaling pathway, and the function could be associated with liver disease treatment. Then, the pharmacological action of GH was evaluated in vitro and in vivo. The treatment with GH significantly increased the protein levels of NRF2 and promoted the transcription of NRF2 downstream genes. Further analysis suggested that GH regulated NRF2 through an autophagy-mediated non-canonical mechanism. Additionally, the administration of GH effectively protected the liver from carbon tetrachloride (CCl 4)-induced liver fibrosis and inflammation, which depended on the activation of NRF2 in hepatic stellate cells and inflammatory cells respectively. Collectively, our findings underscore the potential therapeutic effect of GH on alleviating hepatic fibrosis and inflammation through the augmentation of NRF2 signaling pathway, providing a promising avenue for the treatment of liver fibrosis and inflammation in clinical settings. [Display omitted] • GH is identified as a functional NRF2 activator in vitro and in vivo. • GH enhances NRF2 signaling via autophagy-mediated non-canonical pathway. • GH alleviates hepatic fibrosis and inflammation in a NRF2-depedent manner. [ABSTRACT FROM AUTHOR]

Abstract Background Nonalcoholic fatty liver disease (NAFLD) has developed as a leading public wellness challenge as a result of changes in dietary patterns. Unfortunately, there is still a lack of effective pharmacotherapy methods for NAFLD. Wang’s empirical formula (WSF) has demonstrated considerable clinical efficacy in treating metabolic disorders for years. Nevertheless, the protective effect of WSF against NAFLD and its underlying mechanism remains poorly understood. Methods The NAFLD model was established using a 17-week high-sucrose and high-fat (HSHF) diet with 32 ICR mice. In assessing the therapeutic efficacy of WSF on NAFLD, we detected changes in body weight, viscera weight, biomarkers of glycolipid metabolism in serum and liver, transaminase levels and histopathology of liver with H&E and Oil Red O staining after oral administration. The chemical components in WSF were extensively identified and gathered utilizing the HPLC-Q-TOF/MS system, database mining from HMDB, MassBank, and TCMSP databases, alongside literature searches from CNKI, Wanfang and VIP databases. The forecast of network pharmacology approach was then utilized to investigate the probable mechanisms by which WSF improves NAFLD based on the performance of prospective target identification and pathway enrichment analysis. Besides, molecular docking was also conducted for the verification of combination activities between active components of WSF and core proteins related to NAFLD. In final, validation experiments of obtained pathways were conducted through ELISA, immunohistochemistry (IHC), and western blot (WB) analysis. Results Pharmacodynamic outcomes indicated that WSF intervention effectively mitigated obesity, fat accumulation in organs, lipid metabolism disorders, abnormal transaminase levels and liver pathology injury in NAFLD mice (P

Objective: To evaluate the anti-inflammatory effect of black cumin seed oil (BCSO) and its nanoemulsion on lipopolysaccharide (LPS)-induced liver injury in mice. Methods: LPS-induced acute liver injury mouse model was used to evaluate the effects of BCSO and its nanoemulsion formulation on liver function. Hepatic inflammatory markers including Toll-like receptor 4 (TLR4), interleukin(IL)-1β, heme-oxygenase 1, BAX, and BCL-2 were assessed using real-time PCR. Additionally, protein levels of reduced glutathione, tumor necrosis factor-α, and IL-6 were measured using ELISA, and histological analysis was performed. Indomethacin was used as a standard positive control for comparison. Results: BCSO reduced LPS-induced liver injury and exhibited strong anti-inflammatory effects by downregulating the expression of TLR4, IL-1β, IL-6, tumor necrosis factor-α, and heme-oxygenase 1. Additionally, BCSO demonstrated antioxidant properties by increasing reduced glutathione protein levels and decreasing key apoptotic markers BAX and BCL-2 in hepatocytes. The nanoemulsion formulation further enhanced these anti-inflammatory, antioxidant, and anti-apoptotic effects, and histological examination confirmed this effect. Combining BCSO with indomethacin at a lower dose improved efficacy, thereby reducing its potential side effects. Conclusions: The investigation reveals the anti-inflammatory impact of BCSO and its nanoemulsion formulation on LPS-induced liver oxidative stress, inflammation, and apoptosis.

BACKGROUND & AIMS: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive. METHODS: A mouse model of hepatic ischaemia-reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice. RESULTS: RIPK3M-KO diminished IR stress-induced liver damage with reduced serum alanine aminotransferase/aspartate aminotransferase levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the RIPK3FL/FL controls. IR stress activated RIPK3, inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), x-box binding protein 1 (XBP1), nucleotide-binding oligomerisation domain-containing protein 1 (NOD1), NF-κB, forkhead box O1 (Foxo1), calcineurin A, and TRPM7 in ischaemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, calcineurin A, and TRPM7 activation with reduced serum tumour necrosis factor α (TNF-α) levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation coupled with massively parallel sequencing revealed that macrophage Foxo1 colocalised with XBP1 and activated its target gene Zc3h15 (zinc finger CCCH domain-containing protein 15). Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte calcineurin/TRPM7 activation, with reduced reactive oxygen species production and lactate dehydrogenase release after macrophage/hepatocyte coculture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and cell death. CONCLUSIONS: Macrophage RIPK3 activates the IRE1α-XBP1 pathway and Foxo1 signalling in IR-stress livers. The XBP1-Foxo1 interaction is essential for modulating target gene Zc3h15 function, which is crucial for the control of NOD1 and calcineurin-mediated TRPM7 activation. XBP1 functions as a transcriptional coactivator of Foxo1 in regulating NOD1-driven liver inflammation and calcineurin/TRPM7-induced cell death. Our findings underscore a novel role of macrophage RIPK3 in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. IMPACT AND IMPLICATIONS: Macrophage RIPK3 promotes NOD1-dependent inflammation and calcineurin/TRPM7-induced cell death cascade by triggering the XBP1-Foxo1 axis and its target gene Zc3h15, which is crucial for activating NOD1 and calcineurin/TRPM7 function, implying the potential therapeutic targets in stress-induced liver inflammatory injury.

Abstract Background Chronic hepatitis B virus (HBV) infection remains a serious health issue, and determining the optimal time for antiviral therapy is challenging. We aimed to assess liver histological changes in patients with HBeAg-positive chronic hepatitis B (CHB) and those with HBeAg-negative CHB who had persistently normal alanine aminotransferase and to determine the association between significant liver injury and various clinical parameters. Methods We retrospectively included, in this study, 339 treatment-naïve patients with chronic HBV infections who had persistently normal alanine aminotransferase and underwent liver biopsy from 2013 to 2023. Histologic assessment was based on the Metavir scoring system to evaluate the association between clinical characteristics and the severity of liver inflammation and fibrosis. Results Among the included participants, 138 were HBeAg-positive and 201 were HBeAg-negative. Lower hepatitis B surface antigen (HBsAg) (P = 0.003) and higher aspartate aminotransferase (AST) (P = 0.002) levels were associated with significant necroinflammation, whereas increasing age (P = 0.004) and lower HBV DNA (P

Liver inflammation is frequently linked to oxidative stress and dysregulation of bile acid and fatty acid metabolism. This review focuses on the farnesoid X receptor (FXR), a critical regulator of bile acid homeostasis, and its interaction with the nuclear factor erythroid 2-related factor 2 (Nrf2), a key modulator of cellular defense against oxidative stress. The review explores the interplay between FXR and Nrf2 in liver inflammatory diseases, highlighting the potential therapeutic effects of natural FXR agonists. Specifically, compounds such as auraptene, cafestol, curcumin, fargesone A, hesperidin, lycopene, oleanolic acid, resveratrol, rutin, ursolic acid, and withaferin A are reviewed for their ability to modulate both the FXR and Nrf2 pathways. This article discusses their potential to alleviate liver inflammation, oxidative stress, and damage in diseases such as metabolic-associated fatty liver disease (MAFLD), cholestatic liver injury, and viral hepatitis. In addition, we address the molecular mechanisms driving liver inflammation, including oxidative stress, immune responses, and bile acid accumulation, while also summarizing relevant experimental models. This review emphasizes the promising therapeutic potential of targeting both the Nrf2 and FXR pathways using natural compounds, paving the way for future treatments for liver diseases. Finally, the limitations of the clinical application were indicated, and further research directions were proposed. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods Results Conclusions Since its discovery, the patatin‐like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation‐induced fibrosis.Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo‐apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP‐1, LXRα and TGFβ activity and signalling.The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B virus (HBV) infection remains a serious health issue, and determining the optimal time for antiviral therapy is challenging. We aimed to assess liver histological changes in patients with HBeAg-positive chronic hepatitis B (CHB) and those with HBeAg-negative CHB who had persistently normal alanine aminotransferase and to determine the association between significant liver injury and various clinical parameters. Methods: We retrospectively included, in this study, 339 treatment-naïve patients with chronic HBV infections who had persistently normal alanine aminotransferase and underwent liver biopsy from 2013 to 2023. Histologic assessment was based on the Metavir scoring system to evaluate the association between clinical characteristics and the severity of liver inflammation and fibrosis. Results: Among the included participants, 138 were HBeAg-positive and 201 were HBeAg-negative. Lower hepatitis B surface antigen (HBsAg) (P = 0.003) and higher aspartate aminotransferase (AST) (P = 0.002) levels were associated with significant necroinflammation, whereas increasing age (P = 0.004) and lower HBV DNA (P < 0.001) levels were associated with significant fibrosis in HBeAg-positive patients with normal ALT levels. Higher HBV-DNA (P = 0.001) and AST levels(P < 0.001) were associated with significant necroinflammation, and higher AST(P < 0.001) levels were associated with significant fibrosis in HBeAg-negative patients. Conclusions: A substantial proportion of patients with HBV infection who had normal ALT presented significant liver injury. HBsAg and AST were independent predictive factors for evaluating inflammation, while HBV DNA load and age were independent predictive factors for evaluating fibrosis in the HBeAg-positive group. HBV DNA load and AST were independent predictive factors for evaluating inflammation, while AST were independent predictive factors for evaluating fibrosis in the HBeAg-negative group. [ABSTRACT FROM AUTHOR]

Magnetic resonance elastography (MRE) is recognized as the most precise imaging technology for assessing liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the clinical factors and pathological characteristics that may impact LSM in MASLD patients. This cross-sectional study recruited 124 patients who concurrently performed MRE, MRI-PDFF, and biopsy-proven MASLD. Linear regression models, Spearman's correlation, and subgroup analysis were employed to identify the variables affecting LSM. The AUROC (95 % CI) of MRE for diagnosing fibrosis stage ≥ 1, 2, 3, and 4 was 0.80 (0.70–0.90), 0.76 (0.66–0.85), 0.92 (0.86–0.99), and 0.99 (0.99–1.00), with corresponding cutoffs of 2.56, 2.88, 3.35, and 4.76 kPa, respectively. Multivariate analyses revealed that AST was the only independent clinical variable significantly correlated with LSM. Furthermore, LSM exhibited a notable association with the grade of lobular inflammation and hepatocellular ballooning. Subgroup analysis showed that when AST ≥ 2 ULN or inflammation grade ≥ 2, LSM of patients with early fibrosis stages showed a slight but significant increase. MRE demonstrates significant diagnostic accuracy in predicting liver fibrosis stages for MASLD patients, especially for advanced liver fibrosis and cirrhosis. However, elevated AST and the severity of liver inflammation may impact its accuracy in staging early liver fibrosis. [ABSTRACT FROM AUTHOR]

Cystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond to lipopolysaccharide with excessive inflammation. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD. Wild-type (WT), whole-body Cftr knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (single-cell RNA sequencing), inflammatory mediators were analysed by proteome array, faecal microbiota by 16S ribosomal RNA sequencing and gut permeability by FITC-dextran assay. The livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. Single-cell RNA sequencing analysis of periportal cells showed increased presence of neutrophils, macrophages and T cells, and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis. Defective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease. Severe cystic fibrosis-related liver disease (CFLD) affects 10% of patients with cystic fibrosis (CF) and contributes to increased morbidity and mortality. Treatment options remain limited due to a lack of understanding of disease pathophysiology. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates Cl− and HCO 3 − secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in Cftr -knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF. [Display omitted] • The CF gut microbiota features reduced diversity and increased Enterobacteriales. • Gut dysbiosis in CF is associated with gut inflammation and increased permeability. • Intestinal CFTR deficiency is key to the development of liver disease in CF mice. • Restoring intestinal CFTR or modulating microbiota may improve liver disease in CF. [ABSTRACT FROM AUTHOR]

The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD. Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes. Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4 -knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content. FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD. [Display omitted] • Hepatic FNDC4 expression is decreased in patients with MASLD. • FNDC4 gene silencing promotes hepatocyte apoptosis. • FNDC4 treatment prevents TNF-α-induced hepatocyte inflammatory cell death via AMPKα. • FNDC4 reduces hepatocyte mitochondrial damage improving mitochondrial biogenesis, dynamics and OXPHOS protein expression. [ABSTRACT FROM AUTHOR]

Liver diseases have a global prevalence of 25%, accounting for 4% of all deaths worldwide, and are associated with a 36% increased risk of fatal and nonfatal cardiovascular events. Metabolic dysfunction-associated steatotic liver disease constitutes the liver expression of metabolic syndrome and represents the primary type of liver disease. Microscopical analysis of biopsies, which allows the evaluation of a small portion of tissue with inferences made to the entire organ, is considered the gold standard for determining the presence of liver diseases. However, potential sampling errors in liver biopsies are conceivable because the obtained tissue represents only a tiny fraction of the entire liver mass and may not accurately reflect the true pathological state. Studies have demonstrated the existence of sampling errors in liver biopsies, particularly concerning the severity of inflammation, degree of fibrosis, and the presence of cirrhosis. Also, clinical studies have shown that histopathological abnormalities are better detected in humans when liver samples are collected from both the right and the left lobes. However, a gap exists in clinical investigation to clarify the role of differences between these lobes in improving the diagnostic and prognostic for liver diseases. Building upon the heterogeneous nature of pathological alterations observed in liver lobes, this perspective review provided recommendations to enhance the precision of diagnosis and prognostic accuracy of liver diseases. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the effects of licorice processing of different Evodiae Fructus (EF) specifications on liver inflammation and oxidative stress associated with the intestinal mucosal microbiota. Materials and methods: The 25 Kunming mice were divided into control (MCN), raw small-flowered Evodiae Fructus (MRSEF), raw medium-flowered EF (MRMEF), licorice-processed small-flowered EF (MLSEF), and licorice-processed medium-flowered EF (MLSEF) groups. The EF intervention groups were given different specifications of EF extract solutions by gavage. After 21 days, indices of liver inflammation and oxidative stress and intestinal mucosal microbiota were measured in mice. Results: Compared with the MCN, malondialdehyde (MDA), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) levels were significantly increased in the MRMEF. Although the trends of oxidative stress and inflammatory indexes in the MLSEF and MLMEF were consistent with those in the raw EF groups, the changes were smaller than those in the raw EF groups. Compared to the raw EF groups, the MLSEF and MLMEF showed closer approximations of metabolic function to the MCN. The abundance of Corynebacterium in MRMEF was significantly lower than that in the MCN, and it was not significantly different from the MCN after licorice processing. The probiotic Candidatus Arthromitus was enriched in the MLSEF. The probiotic Lactobacillus was enriched in the MLMEF. Correlation analysis revealed significant negative correlations between IL-1b, some metabolic functions and Corynebacterium. Conclusion: The effects of medium-flowered EF on oxidative stress and inflammatory factors in the liver of mice were stronger than those of small- flowered EF. The licorice processing can reduce this difference by modulating the abundance of Corynebacterium and intestinal mucosal metabolic function. [ABSTRACT FROM AUTHOR]

Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression. [ABSTRACT FROM AUTHOR]

Background: Routine liver function tests capture information about the metabolic and inflammatory condition of the liver, but we lack sensitive biomarkers of early hepatocyte stress. In humans, soluble CD46 (sCD46) levels in blood were recently identified as an accurate biomarker of hepatic steatosis. Here, we explore the diagnostic utility of sCD46 in other liver diseases. Methods: We developed, optimised and validated an ELISA that facilitates measurements of human sCD46 in plasma, serum and culture supernatants. Then, we analysed mechanisms that lead to the release of sCD46 and identified its role in various hepatic stress conditions. Results: We discovered that prostaglandin E2 (PGE2) drives upregulation of matrix metalloproteinase (MMP)-1 in fat-loaded hepatocytes, leading to proteolytic shedding of CD46. We further found that sCD46 release was increased by viral, toxic and hypoxic stresses. Conclusions: sCD46 appears to be a promising biomarker with potential applications in the detection of early liver diseases or monitoring therapeutic responses, which could complement established diagnostic algorithms because sCD46 release is uniquely responsive to hepatocyte stress.

Inflammation responses have identified as a key mediator of in various liver diseases with high morbidity and mortality. cGAS-STING signalling is essential in innate immunity since it triggers release of type I interferons and various of proinflammatory cytokines. The potential connection between cGAS-STING pathway and liver inflammatory diseases has recently been reported widely. In our review, the impact of cGAS-STING on liver inflammation and regulatory mechanism are summarized. Furthermore, many inhibitors of cGAS-STING signalling as promising agents to cure liver inflammation are also explored in detail. A comprehensive knowledge of molecular mechanisms of cGAS-STING signalling in liver inflammation is vital for exploring novel treatments and providing recommendations and perspectives for future utilization.

IntroductionMitochondrial membrane potential (MMP) and mitochondrial mass (MM) affect mitochondrial function and lymphocyte activation, but few studies on HBV infection exist. This study aimed to investigate the regulatory mechanism of mitochondrial dysfunction during HBV infection and its clinical significance by analyzing the alterations of MM and MMPlow in peripheral blood immune cells.MethodsThe study enrolled 90 participants, including healthy volunteers(HC) and patients with HBV infection, HBV patients were divided into chronic hepatitis B patients (CHB) and liver cirrhosis (LC) according to the study, and CHB was also divided into an inflammation group and a non-inflammation group. Flow cytometry was used to analyze the changes of MM and MMPlow in peripheral blood immune cells. These analyses were correlated with the presence of CHB and LC and indexes related to liver inflammation.ResultsThe study revealed significant variations in the percentage of MMPlow and MM of CD8+T cells associated with the progression of the disease. The MMPlow percentage of CD8+T cells in the LC group exhibited a notable decrease compared to the HC group and CHB groups. Moreover, MMPlow of CD8+T cells demonstrated potential in distinguishing CHB and LC (AUC=0.7341, P=0.0032). Furthermore, in exploring the link between mitochondrial function of immune cells and liver inflammation, the study found a negative correlation between the MMPlow ratio of CD4+T and CD8+T cells and AST (p=0.0039 and P=0.0070, r=-0.4405 and r=-0.4146), while the MM of CD8+T cells displayed a positive correlation with AST (p=0.0013, r=0.4865). In CHB patients with normal ALT but liver inflammation detected on B-scan ultrasonography, a significant decrease was observed in the MMPlow percentage of CD8+T (66.13 ± 14.27), CD56+NK(57.77 ± 17.40) and CD4-CD8-T (61.98 ± 15.98) cells. Furthermore, it was also found that the percentage of MMPlow in CD4-CD8-T cells could serve as an indicator for early liver inflammation and injury (AUC=0.8408, P=0.0052).DiscussionIn this study, we conducted a systematic analysis of the percentage of lymphocyte MMPlow and MM in various stages of HBV infection. Our findings revealed a correlation between MMPlow and MM and early liver inflammation, as well as the progression of the infection. This study marked the first demonstration of the clinical diagnostic value of MMPlow and MM in HBV infection. Furthermore, this was the first study to discuss the mitochondria of lymphocytes and liver inflammation in HBV infection. It enhanced the understanding of the role of T cells in liver inflammation, and elucidated potential markers for the early detection of liver injury and clinical cirrhosis.

Epidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.

Abstract The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl4-induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis.

Abstract Background Changes in plasma protein glycosylation are known to functionally affect proteins and to associate with liver diseases, including cirrhosis and hepatocellular carcinoma. Autoimmune hepatitis (AIH) is a liver disease characterized by liver inflammation and raised serum levels of IgG, and is difficult to distinguish from other liver diseases. The aim of this study was to examine plasma and IgG-specific N-glycosylation in AIH and compare it with healthy controls and other liver diseases. Methods In this cross-sectional cohort study, total plasma N-glycosylation and IgG Fc glycosylation analysis was performed by mass spectrometry for 66 AIH patients, 60 age- and sex-matched healthy controls, 31 primary biliary cholangitis patients, 10 primary sclerosing cholangitis patients, 30 non-alcoholic fatty liver disease patients and 74 patients with viral or alcoholic hepatitis. A total of 121 glycans were quantified per individual. Associations between glycosylation traits and AIH were investigated as compared to healthy controls and other liver diseases. Results Glycan traits bisection (OR: 3.78 [1.88–9.35], p-value: 5.88 × 10− 3), tetraantennary sialylation per galactose (A4GS) (OR: 2.88 [1.75–5.16], p-value: 1.63 × 10− 3), IgG1 galactosylation (OR: 0.35 [0.2–0.58], p-value: 3.47 × 10− 5) and hybrid type glycans (OR: 2.73 [1.67–4.89], p-value: 2.31 × 10− 3) were found as discriminators between AIH and healthy controls. High A4GS differentiated AIH from other liver diseases, while bisection associated with cirrhosis severity. Conclusions Compared to other liver diseases, AIH shows distinctively high A4GS levels in plasma, with potential implications on glycoprotein function and clearance. Plasma-derived glycosylation has potential to be used as a diagnostic marker for AIH in the future. This may alleviate the need for a liver biopsy at diagnosis. Glycosidic changes should be investigated further in longitudinal studies and may be used for diagnostic and monitoring purposes in the future.

We have previously documented that in liver cells, the multifunctional protein scaffold p62/SQSTM1 is closely associated with IκBα, an inhibitor of the transcriptional activator NF-κB. Such an intimate p62-IκBα association we now document leads to a marked 18-fold proteolytic IκBα-stabilization, enabling its nuclear entry and termination of the NF-κB-activation cycle. In p62-/--cells, such termination is abrogated resulting in the nuclear persistence and prolonged activation of NF-κB following inflammatory stimuli. Utilizing various approaches both classic (structural deletion, site-directed mutagenesis) as well as novel (in-cell chemical crosslinking), coupled with proteomic analyses, we have defined the precise structural hotspots of p62-IκBα association. Accordingly, we have identified such IκBα hotspots to reside around N-terminal (K38, K47, and K67) and C-terminal (K238/C239) residues in its fifth ankyrin repeat domain. These sites interact with two hotspots in p62: One in its PB-1 subdomain around K13, and the other comprised of a positively charged patch (R183/R186/K187/K189) between its ZZ- and TB-subdomains. APEX proximity analyses upon IκBα-cotransfection of cells with and without p62 have enabled the characterization of the p62 influence on IκBα-protein-protein interactions. Interestingly, consistent with p62's capacity to proteolytically stabilize IκBα, its presence greatly impaired IκBα's interactions with various 20S/26S proteasomal subunits. Furthermore, consistent with p62 interaction with IκBα on an interface opposite to that of its NF-κB-interacting interface, p62 failed to significantly affect IκBα-NF-κB interactions. These collective findings together with the known dynamic p62 nucleocytoplasmic shuttling leads us to speculate that it may be involved in "piggy-back" nuclear transport of IκBα following its NF-κB-elicited transcriptional activation and de novo synthesis, required for termination of the NF-κB-activation cycle. Consequently, mice carrying a liver-specific deletion of p62-residues 68 to 252 reveal age-dependent-enhanced liver inflammation. Our findings reveal yet another mode of p62-mediated pathophysiologically relevant regulation of NF-κB.

The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl4-induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) are responsible for liver fibrosis accompanied by its activation into myofibroblasts and the abundant production of extracellular matrix. However, the HSC contribution to progression of liver inflammation has been less known. We aimed to elucidate the mechanism in HSCs underlying the inflammatory response and the function of tumor necrosis factor α‐related protein A20 (TNFAIP3). We established A20 conditional knockout (KO) mice crossing Twist2‐Cre and A20 floxed mice. Using these mice, the effect of A20 was analyzed in mouse liver and HSCs. The human HSC line LX‐2 was also used to examine the role and underlying molecular mechanism of A20. In this KO model, A20 was deficient in >80% of HSCs. Spontaneous inflammation with mild fibrosis was found in the liver of the mouse model without any exogenous agents, suggesting that A20 in HSCs suppresses chronic hepatitis. Comprehensive RNA sequence analysis revealed that A20‐deficient HSCs exhibited an inflammatory phenotype and abnormally expressed chemokines. A20 suppressed JNK pathway activation in HSCs. Loss of A20 function in LX‐2 cells also induced excessive chemokine expression, mimicking A20‐deficient HSCs. A20 overexpression suppressed chemokine expression in LX‐2. In addition, we identified DCLK1 in the genes regulated by A20. DCLK1 activated the JNK pathway and upregulates chemokine expression. DCLK1 inhibition significantly decreased chemokine induction by A20‐silencing, suggesting that A20 controlled chemokine expression in HSCs via the DCLK1–JNK pathway. In conclusion, A20 suppresses chemokine induction dependent on the DCLK1–JNK signaling pathway. These findings demonstrate the therapeutic potential of A20 and the DCLK1–JNK pathway for the regulation of inflammation in chronic hepatitis. [ABSTRACT FROM AUTHOR]

Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH. [ABSTRACT FROM AUTHOR]

Background: The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology. Methods: We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation. Results: In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700, p < 0.001). Conclusions: The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage. [ABSTRACT FROM AUTHOR]

The rs72613567:TA polymorphism in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we sought to define the pathogenic role of HSD17B13 in triggering liver inflammation. Here, we demonstrate that HSD17B13 forms liquid–liquid phase separation (LLPS) around lipid droplets in the livers of MASH patients. The dimerization of HSD17B13 supports the LLPS formation and promotes its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Blockade of the PAF receptor or STAT3 pathway inhibits the fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbates western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13−/− mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease. [ABSTRACT FROM AUTHOR]

Background: Changes in plasma protein glycosylation are known to functionally affect proteins and to associate with liver diseases, including cirrhosis and hepatocellular carcinoma. Autoimmune hepatitis (AIH) is a liver disease characterized by liver inflammation and raised serum levels of IgG, and is difficult to distinguish from other liver diseases. The aim of this study was to examine plasma and IgG-specific N-glycosylation in AIH and compare it with healthy controls and other liver diseases. Methods: In this cross-sectional cohort study, total plasma N-glycosylation and IgG Fc glycosylation analysis was performed by mass spectrometry for 66 AIH patients, 60 age- and sex-matched healthy controls, 31 primary biliary cholangitis patients, 10 primary sclerosing cholangitis patients, 30 non-alcoholic fatty liver disease patients and 74 patients with viral or alcoholic hepatitis. A total of 121 glycans were quantified per individual. Associations between glycosylation traits and AIH were investigated as compared to healthy controls and other liver diseases. Results: Glycan traits bisection (OR: 3.78 [1.88–9.35], p-value: 5.88 × 10− 3), tetraantennary sialylation per galactose (A4GS) (OR: 2.88 [1.75–5.16], p-value: 1.63 × 10− 3), IgG1 galactosylation (OR: 0.35 [0.2–0.58], p-value: 3.47 × 10− 5) and hybrid type glycans (OR: 2.73 [1.67–4.89], p-value: 2.31 × 10− 3) were found as discriminators between AIH and healthy controls. High A4GS differentiated AIH from other liver diseases, while bisection associated with cirrhosis severity. Conclusions: Compared to other liver diseases, AIH shows distinctively high A4GS levels in plasma, with potential implications on glycoprotein function and clearance. Plasma-derived glycosylation has potential to be used as a diagnostic marker for AIH in the future. This may alleviate the need for a liver biopsy at diagnosis. Glycosidic changes should be investigated further in longitudinal studies and may be used for diagnostic and monitoring purposes in the future. [ABSTRACT FROM AUTHOR]

Background & aimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcoholactivated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IαB&, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Introduction: The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis. Methods: C57BL/6, ST2-deficient (Il1rl1-/-) and Areg-/- mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre+ x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2+ Tregs and ILC2s were investigated in vitro. Immune cell phenotype was analyzed by flow cytometry. Results and discussion: We identified IL-33-responsive ST2+ Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1-/- mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2+ Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2+ Tregs and ILC2s in immune-mediated hepatitis. Areg-/- mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2+ Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2+ Treg activation in vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre+ x ST2fl/fl mice lacking ST2+ Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2+ Tregs and reinforcing their immunosuppressive capacity in liver inflammation. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition observed globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Currently, the US Food and Drug Administration (FDA) has not approved any drugs for the treatment of NAFLD. NAFLD is characterized by histopathological abnormalities in the liver, such as lipid accumulation, steatosis, hepatic balloon degeneration, and inflammation. Dysbiosis of the gut microbiota and its metabolites significantly contribute to the initiation and advancement of NAFLD. Bacteroides, a potential probiotic, has shown strong potential in preventing the onset and progression of NAFLD. However, the precise mechanism by which Bacteroides treats NAFLD remains uncertain. In this review, we explore the current understanding of the role of Bacteroides and its metabolites in the treatment of NAFLD, focusing on their ability to reduce liver inflammation, mitigate hepatic steatosis, and enhance intestinal barrier function. Additionally, we summarize how Bacteroides alleviates pathological changes by restoring the metabolism, improving insulin resistance, regulating cytokines, and promoting tight-junctions. A deeper comprehension of the mechanisms through which Bacteroides is involved in the pathogenesis of NAFLD should aid the development of innovative drugs targeting NAFLD. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications. [ABSTRACT FROM AUTHOR]

Background: Water T1 of the liver has been shown to be promising in discriminating the progressive forms of fatty liver diseases, inflammation, and fibrosis, yet proper correction for iron and lipid is required. Purpose: To examine the feasibility of an empirical approach for iron and lipid correction when measuring imaging‐based T1 and to validate this approach by spectroscopy on in vivo data. Study Type: Retrospective. Population: Next to mixed lipid‐iron phantoms, individuals with different hepatic lipid content were investigated, including people with type 1 diabetes (N = 15, %female = 15.6, age = 43.5 ± 14.0), or type 2 diabetes mellitus (N = 21, %female = 28.9, age = 59.8 ± 9.7) and healthy volunteers (N = 9, %female = 11.1, age = 58.0 ± 8.1). Field Strength/Sequences: 3 T, balanced steady‐state free precession MOdified Look‐Locker Inversion recovery (MOLLI), multi‐ and dual‐echo gradient echo Dixon, gradient echo magnetic resonance elastography (MRE). Assessment: T1 values were measured in phantoms to determine the respective correction factors. The correction was tested in vivo and validated by proton magnetic resonance spectroscopy (1H‐MRS). The quantification of liver T1 based on automatic segmentation was compared to the T1 values based on manual segmentation. The association of T1 with MRE‐derived liver stiffness was evaluated. Statistical Tests: Bland–Altman plots and intraclass correlation coefficients (ICCs) were used for MOLLI vs. 1H‐MRS agreement and to compare liver T1 values from automatic vs. manual segmentation. Pearson's r correlation coefficients for T1 with hepatic lipids and liver stiffness were determined. A P‐value of 0.05 was considered statistically significant. Results: MOLLI T1 values after correction were found in better agreement with the 1H‐MRS‐derived water T1 (ICC = 0.60 [0.37; 0.76]) in comparison with the uncorrected T1 values (ICC = 0.18 [−0.09; 0.44]). Automatic quantification yielded similar liver T1 values (ICC = 0.9995 [0.9991; 0.9997]) as with manual segmentation. A significant correlation of T1 with liver stiffness (r = 0.43 [0.11; 0.67]) was found. A marked and significant reduction in the correlation strength of T1 with liver stiffness (r = 0.05 [−0.28; 0.38], P = 0.77) was found after correction for hepatic lipid content. Data Conclusion: Imaging‐based correction factors enable accurate estimation of water T1 in vivo. Level of Evidence: 1 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases. [ABSTRACT FROM AUTHOR]

Dietary soy protein and soy isoflavones have anti-inflammatory properties. Previously, we reported that feeding soy protein concentrate diet (SPC) with low or high isoflavone (LIF or HIF) to young (seven-week-old) obese (fa/fa) Zucker rats inhibits lipopolysaccharide (LPS) translocation and decreases liver inflammation compared to a casein control (CAS) diet. The current study investigated whether SPC-LIF and SPC-HIF diets would reduce liver inflammation in adult obese Zucker rats fed a CAS diet. A total of 21 six-week-old male obese (fa/fa) Zucker rats were given CAS diet for 8 weeks to develop obesity then randomly assigned to CAS, SPC-LIF, or SPC-HIF (seven rats/group) diet for an additional 10 weeks. The expression of LPS-translocation, inflammation, and intestinal permeability markers were quantified by qPCR in liver, visceral adipose tissue (VAT), and colon. LPS concentration was determined in both the colon content and fecal samples by a Limulus amebocyte lysate (LAL) test. SPC-LIF and SPC-HIF diets significantly decreased liver LPS-binding protein (LBP) expression compared to CAS diet (p < 0.01 and p < 0.05, respectively). SPC-HIF diet also significantly decreased liver MCP-1 and TNF-α expression (p < 0.05) and had a trend to decrease liver iNOS expression (p = 0.06). In the colon, SPC-HIF diet significantly increased LBP expression compared to CAS diet (p < 0.05). When samples from all three groups were combined, there was a negative correlation between colon LBP expression and liver LBP expression (p = 0.046). SPC diets did not alter the expression of intestinal permeability markers (i.e., occludin, claudin 3, and zonula occludens-1) in the colon or inflammation markers (i.e., TNF-α and iNOS) in VAT or the colon. LPS levels in the colon content did not differ between any groups. Fecal LPS levels were significantly higher in the SPC-LIF and SPC-HIF groups compared to the CAS group (p < 0.01). In conclusion, SPC, particularly SPC with HIF, reduces liver LBP expression and inflammation makers (i.e., TNF-α and MCP-1 expression) in adult obese Zucker rats, likely by reducing LPS translocation. [ABSTRACT FROM AUTHOR]

Inflammatory bowel conditions can involve nearly all organ systems and induce pathological processes through increased oxidative stress, lipid peroxidation and disruption of the immune response. Patients with inflammatory bowel disease (IBD) are at high risk of having extra-intestinal manifestations, for example, in the hepatobiliary system. In 30% of patients with IBD, the blood values of liver enzymes, such as AST and ALT, are increased. Moreover, treatments for inflammatory bowel diseases may cause liver toxicity. Apple polyphenol extracts are widely acknowledged for their potential antioxidant effects, which help prevent damage from oxidative stress, reduce inflammation, provide protection to the liver, and enhance lipid metabolism. The aim of this study was to investigate whether the polyphenol apple extract from Malus domestica cv. 'Limoncella' (LAPE) may be an effective intervention for the treatment of IBD-induced hepatotoxicity. The LAPE was administrated in vivo by oral gavage (3–300 mg/kg) once a day for 3 consecutive days, starting 24 h after the induction of dinitro-benzenesulfonic acid (DNBS) colitis in mice. The results showed that LAPE significantly attenuated histological bowel injury, myeloperoxidase activity, tumor necrosis factor and interleukin (IL-1β) expressions. Furthermore, LAPE significantly improved the serum lipid peroxidation and liver injury in DNBS-induced colitis, as well as reduced the nuclear transcription factor-kappaB activation. In conclusion, these results suggest that LAPE, through its antioxidant and anti-inflammatory properties, could prevent liver damage induced by inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic autoimmune disease characterized by immune-mediated destruction of intrahepatic small bile ducts. CD8 T cells play a critical role in biliary destruction. However, regulatory T cells (Tregs) have also been identified in the portal tracts of PBC patients. This study tested the hypothesis that hepatic Tregs in PBC were dysfunctional in suppressing immune responses in disease by using our human PBC-like autoimmune cholangitis (AIC) mouse model induced by 2-octynoic acid-conjugated ovalbumin (2-OA-OVA). Our results showed that female and male mice immunized with 2-OA-OVA developed AIC; however, female AIC mice had more severe liver inflammation and fibrosis than male AIC mice. Levels of functional effector CD8 T cells and their chemoattractants, CXCL9 and CXCL10, in the liver were markedly elevated in female AIC mice than in male AIC mice. These results reinforce that CD8 T cells are the primary effector cells in PBC. The number of hepatic Tregs in AIC mice was also higher than in saline-treated mice, but there was no difference between male and female AIC mice. The suppressive function of AIC Tregs was evident despite a discrepancy in the changes in their co-inhibitory receptors and inhibitory cytokines. However, the expansion of hepatic Tregs by low-dose IL-2 treatment did not reduce immune responses to AIC, which may be due to the dysfunction of Tregs in inhibiting T cells. In conclusion, the function of Tregs in the inflamed liver of PBC was insufficient, and low-dose IL-2 treatment could not restore their function to suppress pathological immune responses. Transferring normal Tregs or directly targeting effector CD8 T cells may be beneficial for treating PBC. In 2-OA-OVA immunized autoimmune cholangitis (AIC) mice, a model resembling primary biliary cholangitis, elevated levels of functional CD8 T cells and related chemoattractants in the liver were observed, potentially contributing to biliary epithelial cell damage. Additionally, regulatory T cells (Tregs) in the AIC liver demonstrated inadequate suppressive function, even when expanded through low-dose IL-2 treatment. Graphical Abstract [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is characterized by a progressive fibroinflammatory cholangiopathy in early infants with unknown etiology. Although innate immune disorder is involved in its mechanism, role of NLRP3 inflammasome in BA remains largely undefined. To explore the role of NLRP3 inflammasome in BA. The expressions of NLRP3 inflammasome-related genes were determined in BA patients. Role of NLRP3 inflammasome was evaluated using MCC950 in experimental BA. Furthermore, gadolinium chloride, a macrophage scavenger, was applied to validate the inflammasome's cellular localization. Finally, the effects of NLRP3 inflammasome activation on liver fibrosis were explored in vivo and vitro in experimental BA. The components of NLRP3 inflammasome were up-regulated in BA patients. Inflammasome-related genes showed positively correlated with liver inflammation and fibrosis in BA patients. In experimental BA, inflammasome-related genes were up-regulated, and their expressions were inhibited by MCC950, which promoted mice growth, protected liver function, alleviated obstructive jaundice, inhibited liver inflammation, and reduced serum IL-1β level. NLRP3 inflammasome was expressed in macrophages, and macrophage elimination exerted the same protective roles as MCC950 did in BA. Additionally, NLRP3 inflammasome activation promoted liver fibrosis in experimental BA. NLRP3 inflammasome activation in macrophages promoted liver inflammation and fibrosis in experimental BA. [ABSTRACT FROM AUTHOR]