Indole-3-propionic acid (IPA) is documented to improve the effectiveness of tumor immunotherapy via regulating anti-tumor immunity. However, the impacts of IPA in hepatocellular carcinoma (HCC) patients undergoing sintilimab combined with bevacizumab (SCB) treatment remain unknown. This study investigated the effects and underlying mechanisms of IPA in SCB-treated HCC. Serum, tumor tissue, fecal and lymph node tissue samples were collected from HCC patients with or without a response to SCB therapy. Humanized orthotopic and subcutaneous HCC NOG mouse models were established. IPA-treated mouse dendritic cells (DCs) were co-cultured with mouse CD8+ T-cells, which were subsequently co-cultured with Hepa1-6 cells. IPA levels were elevated in the serum, tumor tissues, and feces of responders, and serum IPA levels were positively correlated with the proportion of IFN-γ+CD8+ T cells in tumor tissues as well asac-H3K27 and IL-12A levels in lymph node DCs. IPA amplified the suppressive impact of SCB on tumor growth in HCC mice. Moreover, IPA increased ac-H3K27 and IL-12A levels in DCs and upregulated effector CD8+ T-cell immunity in HCC mice. Administration of a CD8-neutralizing antibody and injection of shIL-12A-transfected DCs weakened IPA-mediated inhibition of HCC in vivo. Furthermore, the ac-H3K27 inhibitor A-485 suppressed IL-12A expression and effector CD8+ T-cell immunity induced by IPA, thereby promoting the proliferation, invasion, and migration of Hepa1-6 cells in vitro. These findings demonstrate that IPA enhances the effect of SCB-treated HCC by upregulating H3K27 acetylation to promote IL-12A expression in DCs, thereby potentiating CD8+ T-cell immunity, which provides a basis for its potential use as a clinical adjuvant therapy.

[This corrects the article DOI: 10.3389/fimmu.2025.1510770.].

Background:Metabolic Syndrome (MetS), defined by central obesity and disturbances in glucose and lipid metabolism, has not been extensively validated in large national cohorts concerning its association with fatty liver disease (FLD), gastrointestinal tumors (GIT), and prognostic outcomes. Methods:A total of 24,434 adults from the 2003-2018 cycles of The National Health and Nutrition Examination Survey (NHANES) were included as the development cohort, with a validation cohort of 365 adults to verify key associations. MetS was diagnosed per NCEP-ATP III criteria across both cohorts. Weighted multivariate regression models assessed associations between MetS and FLD/GIT incidence, and Cox proportional hazards models evaluated survival risks. Three hierarchical models were constructed: Model 1 (unadjusted), Model 2 (adjusted for demographic confounders), and Model 3 (further adjusted for laboratory parameters). Results:In the development cohort, MetS patients exhibited a higher FLD prevalence (16.2% vs. 4.6%) and GIT incidence (1.25% vs. 0.57%). After full adjustment in Model 3, MetS remained a strong independent risk factor for FLD (OR = 3.889, 95% CI: 3.529-4.307) and GIT (OR = 2.456, 95% CI: 1.832-3.292). These associations were corroborated in the validation cohort, with adjusted ORs of 4.760 for FLD and 4.395 for GIT. Survival analysis indicated that MetS significantly reduced overall survival in the development cohort, with HRs for all-cause, cancer-specific, and cardiovascular mortality of 2.146, 1.941, and 2.572, respectively. Furthermore, the mortality risk was further elevated in FLD patients with MetS (all-cause mortality HR = 1.823). In the validation cohort, cardiovascular mortality risk was significant (HR = 3.902), while other survival outcomes did not reach statistical significance due to the small sample size. Sensitivity analysis using IDF criteria confirmed the robustness of these findings. Conclusion:This study confirms that MetS is strongly associated with FLD risk and GIT incidence, supporting early metabolic intervention to interrupt the progression of liver disease and tumors.

The atherogenic index of plasma (AIP) serves as a crucial indicator for assessing atherosclerotic risk. It reflects the degree of dyslipidaemia and cardiovascular disease (CVD) risk. The cardiometabolic index (CMI) provides a comprehensive evaluation of obesity-related metabolic risk, acting as a key biomarker for predicting multiple cardiometabolic diseases. The relationship between AIP and CMI in patients with non-alcoholic fatty liver disease (NAFLD) and mortality or CVD risk remains unclear. This study included 5792 adult (≥ 18 years) NAFLD patients from the US National Health and Nutrition Examination Survey (NHANES, 1999–2018). Weighted logistic regression and Cox proportional hazards models were employed to investigate the association between AIP, CMI and all-cause mortality, CVD mortality and CVD risk. Restricted cubic spline (RCS) curves assessed non-linear associations. Subgroup analyses and mediation analyses examined the effect modifiers and mediators. The incremental predictive value of AIP and CMI was evaluated. Sensitivity analyses were conducted to validate the robustness. During follow-up, 721 all-cause deaths (including 241 CVD deaths) and 726 total CVD events were recorded. After adjusting for confounding factors, patients in the highest quartiles of AIP and CMI had a significantly higher risk of specific CVD events. The strongest association was observed for CHF (AIP: OR = 3.157, 95

Emphysematous pancreatitis (EP) is a severe and life-threatening complication of pancreatitis characterized by gas formation within pancreatic tissues, which often results from bacterial infection. This condition poses significant challenges due to its rapid progression and high mortality rate. Innate immunity plays a pivotal role in the pathogenesis, progression, and potential treatment of EP as the body’s first line of defense against infectious agents. Current research has elucidated various mechanisms through which innate immune components contribute to inflammatory responses and microbial clearance in EP. Despite advances in understanding pancreatic inflammation, the specific contributions of innate immunity to EP’s development, progression, and clinical outcomes remain not fully elucidated. Incorporating insights into innate immune markers may enhance early detection and prognostic accuracy. Moreover, therapeutic strategies targeting innate immune modulation hold promise for improving management and reducing morbidity associated with EP. This review comprehensively summarizes the mechanisms by which innate immune responses contribute to EP pathogenesis. It also highlights emerging diagnostic biomarkers and imaging techniques that facilitate early detection and discusses novel immunomodulatory therapies targeting innate immune responses. This review is a scoping review based on a structured literature search (see Methods). We aim to provide a framework and identify future research directions to improve clinical management and outcomes for patients with EP.

[This corrects the article DOI: 10.3389/fimmu.2025.1565065.].

Objectives: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that inhibits HBV replication by interfering with assembly and disassembly of the virus nucleocapsid, this prospective, open-label, comparative, phase 2b trial evaluated the antiviral activity and safety of GLS4/ritonavir (RTV) combined with entecavir in hepatitis B e antigen-positive patients. Methods: 250 CHB patients were enrolled, including treatment-na & iuml;ve patients and those interrupted anti-HBV drugs for >= 6 months (Part A, n=125), and patients who had taken ETV for >= 1 year and had achieved viral suppression (Part B, n=125). Patients were randomly allocated to receive 120 mg GLS4/100 mg RTV plus 0.5 mg ETV or 0.5 mg ETV monotherapy for 96 weeks. Results: In the mid-term, in Part A (n=122), greater least-squares mean (LSM) changes from baseline were observed in the GLS4/RTV plus ETV cohort than in ETV monotherapy cohort in HBV DNA (-6.28 vs -5.72 log10 IU/ml, p=0.0005), HBsAg (-0.87 vs -0.65 log10 IU/ml, p=0.0653), HBV pgRNA (-3.83 vs -1.91 log10 copies/ml, p<0.0001); The proportions of both HBV DNA and pgRNA negative patients were 17.3% (13/75, GLS4/RTV plus ETV) and 0% (0/30, ETV monotherapy). In Part B (n=123), greater mean LSM reductions in HBsAg (-0.17 vs -0.06 log10 IU/ml, p=0.0013), HBV pgRNA (-1.61 vs -0.28 log10 copies/ml, p<0.0001) were also observed in the GLS4/RTV+ETV cohort. the proportions of both HBV DNA and pgRNA-negative patients were 71.6% (48/67, GLS4/RTV plus ETV) and 18.9% (7/37, ETV monotherapy), respectively. No patients achieved HBsAg loss at week 48. GLS4/RTV + ETV were well tolerated, the most common adverse events were elevated alanine aminotransferase levels and hypertriglyceridemia, which were reversed by temporary GLS4/RTV discontinuation. Conclusions: The primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208). (c) 2025 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Interleukin-36 (IL-36) signaling pathway plays an important regulatory role in inflammatory and infectious diseases. However, the modulatory function of IL-36 in CD8+T cells that are involved in liver cirrhosis with spontaneous bacterial peritonitis (SBP) has not been understood. Sixty-five liver cirrhotic patients (42 untainted ascites and 23 SBP patients) and 20 controls were included. IL-36 levels were measured by ELISA. CD8+T cells were purified from ascites, and were stimulated with IL-36 receptor antagonist (IL-36RA). CD8+T cells were co-cultured with HepG2 cells in direct contact and indirect contact manners. Target cell death and cytotoxic molecules levels were investigated to assess CD8+T cell cytotoxicity. The immune-checkpoint molecules expressions on CD8+T cells were measured by flow cytometry. There were no significant differences in IL-36alpha, IL-36beta, or IL-36gamma levels between untainted ascites and SBP patients. SBP patients had increased ascitic IL-36RA, which positively correlated with alanine aminotransferase and ascitic neutrophil count. IL-36RA stimulation did not affect CD8+T cell proliferation, but dampened CD8+T cell-induced cell death and proinflammatory cytokine secretions. Perforin and granzyme B productions were down-regulated in direct contact manner. IL-36RA stimulation promoted immune-checkpoint molecules expressions on CD8+T cells. The present findings revealed that elevated ascitic IL-36RA might inhibit ascitic CD8+T cell cytotoxicty in liver cirrhotic patients with SBP.

IgG4-related pancreatitis (IRP) is a form of chronic pancreatitis characterized by the infiltration of IgG4-positive plasma cells, representing a pancreatic manifestation of IgG4-related disease (IgG4-RD). In recent years, with the growing understanding of IgG4-RD, the incidence of IRP has shown an increasing trend. This article provides a comprehensive review of the latest advancements in the epidemiology, etiology, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, and treatment of IRP.

BackgroundInflammation is a critical component in the process of resolved hepatitis B virus (HBV) infection. The neutrophil-to-lymphocyte ratio (NLR) serves as a sensitive indicator of systemic inflammation and immune activation. Our study aimed to investigate the correlation between elevated NLR levels and the risk of all-cause mortality in patients with resolved HBV infection. Additionally, we evaluated the potential mediating effect of diabetes mellitus (DM) on this correlation.MethodsOur study enrolled 1,146 adult patients with resolved HBV infection from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. We utilized the Restricted Cubic Splines (RCS) and Maximum Selection Rank Statistical Method (MSRSM) to analyze the relationship between the NLR and the risk of all-cause mortality. The impact of NLR was evaluated using a weighted multivariate Cox regression model, and the model’s predictive accuracy was assessed using time-dependent Receiver Operating Characteristic (ROC) curves. An intermediary analysis was conducted to explore the potential influence of DM on the observed relationship.ResultsDuring follow-up period of 103.54 ± 4.90 months, we recorded 207 deaths among the study participants. The analysis using the RCS method revealed a significant positive correlation between the NLR and the risk of all-cause mortality. Those with elevated NLR levels faced a substantially higher mortality risk compared to those with lower levels, as indicated by a Hazard Ratio (HR) of 1.84, with a 95% Confidence Interval (CI) of 1.17 to 2.89 (p < 0.05). The predictive accuracy of the model was substantial, as evidenced by the Area Under the Curve (AUC) for ROC curves at 3, 5, and 10 years, which were 0.873, 0.870, and 0.862, respectively. Furthermore, mediation analysis indicated that DM significantly influenced the relationship between the NLR and mortality, with a mediation effect of 6.57% (95% Confidence Interval [CI]: 0.64 to 15%; p = 0.02).ConclusionElevated NLR is significantly associated with an increased risk of all-cause mortality in patients with resolved HBV infection. Concurrently, DM acts as a partial mediator of this association.

In recent years, the novel coronavirus infectious disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to over 670 million infections and nearly 7 million deaths worldwide. The global pandemic of COVID-19 has precipitated a significant public health crisis. The prevalence of liver function abnormalities associated with SARS-CoV-2 is as high as 53% among healthy individuals or patients with autoimmune hepatitis (AIH) and shows a positive correlation with disease severity; moreover, specific adaptive immune responses can influence the trajectory and outcomes of COVID-19. For instance, SARS-CoV-2 may impact autoimmunity through mechanisms such as excessive stimulation of immune responses and molecular mimicry, particularly in genetically predisposed individuals. Currently, the overall mutational trend of SARS-CoV-2 indicates heightened infectivity and immune evasion capabilities. Consequently, vaccination remains crucial for universal protection against this disease. Nevertheless, alongside the widespread implementation of vaccination programs globally, an increasing number of cases have been documented where COVID-19 vaccination appears to trigger new-onset autoimmune hepatitis; yet definitive evidence is still pending elucidation regarding causality. In this review, we analyse the clinical-immunological characteristics, risks associated with severe disease progression, and prognosis for AIH patients infected with SARS-CoV-2; discuss the detrimental effects exerted by SARS-CoV-2 on hepatic function; summarise the mechanisms and attributes leading to new-onset AIH; as well as provide insights into how vaccination may interfere with autoimmunity processes. We continue to underscore the significance of vaccination while aiming to enhance awareness concerning potential risks associated with it—this could facilitate better management strategies for autoimmune diseases along with appropriate adjustments in vaccination protocols. Although the precise triggering mechanism linking COVID-19-related events to AIH remains unclear, existing evidence suggests that this relationship is far from coincidental.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for different types of cancers, providing significant clinical benefits. However, these therapies are associated with various immune-related adverse events (irAEs), including hepatic manifestations such as hepatitis, sinusoidal obstruction syndrome (SOS), and nodular regenerative hyperplasia. Among these, regenerative hepatic pseudotumors (RHPs) are exceptionally rare and poorly described in literature. Here, we report the case of a 66-year-old man with metastatic non-small-cell lung cancer (NSCLC) who developed a hepatic pseudotumor during routine imaging following treatment with the anti-programmed cell death 1 (PD-1) therapy, tislelizumab. Despite the presence of a hepatic lesion on imaging, the patient exhibited no clinical symptoms or biochemical evidence of severe immune-mediated hepatitis. Following cessation of anti-PD-1 therapy and initiation of systemic steroid therapy, the hepatic pseudotumors stabilized without further growth. The findings suggest that ICI therapy may be associated with the development of regenerative hepatic pseudotumor (RHP). Given the nonspecific and potentially misleading imaging features of RHP, biopsy is essential for accurate diagnosis and differentiation from malignant lesions such as hepatic metastases. Early histological evaluation through biopsy can prevent unnecessary interventions and guide appropriate management in patients presenting with liver lesions during or after ICI therapy. This case suggests a possible association between the development of RHP and tislelizumab treatment. The effect of ICI-induced hepatic pseudotumors on NSCLC progression is unclear and requires further investigation.

Overlapping primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) represents a distinctive autoimmune phenotype characterized by concurrent cholestatic and hepatocellular damage, culminating in a more aggressive disease course if not recognized. This review synthesizes the existing evidence concerning epidemiology, pathophysiology, and diagnostic criteria, with particular emphasis on histopathology, serological markers, and established scoring systems, including the Paris criteria and the International Autoimmune Hepatitis Group (IAIHG) scoring scheme. We highlight the clinical relevance of combined therapies, typically comprising ursodeoxycholic acid and immunosuppressants, in effectively controlling both components of the disorder and halting fibrosis progression. Additionally, we discuss emerging data regarding second-line agents such as obeticholic acid and innovative immunomodulatory approaches aimed at refining patient outcomes. Special attention is dedicated to pediatric and pregnant populations, in whom disease manifestation and therapeutic responses may differ. Ongoing evaluations of noninvasive biomarkers and imaging modalities, including transient elastography, promise improved monitoring and individualized management strategies. Notably, relevant outcome measures, including quality of life and the burden of pruritus, are paramount for comprehensive patient care. Collectively, these advances hold promise for improved long-term patient survival by enabling more precise diagnostic pathways, targeted therapeutic regimens, and closer surveillance.

Nonalcoholic fatty liver disease(NAFLD),a prevalent liver disorder globally,is strongly associated with insulin resistance,obesity,and metabolic syndrome.As individuals grow older,the likelihood of developing metabolic disorders such as hypertension,hyperlipidemia,and abnormal glucose metabolism increases gradually.NAFLD,which often lacks noticeable symptoms,tends to be overlooked.Therefore,it is important to identify early and effective diagnostic indicators in order to control the progression of the disease.Homocysteine is a known risk factor for several chronic illnesses,including cardiovascular disease,diabetes,and NAFLD.Folic acid and vitamin B12 play a significant role in the metabolism of homocysteine.This paper examines the correlation between the three factors and NAFLD,and presents novel concepts for potential clinical diagnostic and treatment approaches in the future.

Internal medicine teaching content is abstract, covering multiple disciplines, multiple systems, the traditional infusion teaching method is prone to the phenomenon of "doing its own thing" of each discipline, which is not conducive to the development and optimization of medical education.The common teaching ways include problem-based learning (PBL) teaching method and case-based learning (CBL) teaching method.With the development of information technology, internal medicine teaching has gradually entered the multidimensional interactive teaching model under the addition of "Internet +" . The "Internet +" multidimensional interactive teaching combined with PBL and CBL teaching model has many advantages over the traditional teaching model. This paper intends to review the application status of the above two main teaching models in internal medicine teaching and explore the application significance and value of multidimensional interactive teaching model in internal medicine teaching under the background of "Internet +" .

One case involved a 61-year-old woman who was admitted to hospital with liver occupation, subsequently found multiple organ occupation, and was eventually pathologically identified as having immunoglobulin G4-related disease.

INTRODUCTION:Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized as a severe condition with rapid progression, poor therapeutic response and poor prognosis. Early and timely evaluation of the prognosis is helpful for providing appropriate clinical intervention and prolonging patient survival.AREAS COVERED:Currently, there are no specific dynamic and comprehensive approaches to assess the prognosis of patients with ACLF. This article reviews the progress in evaluating the short-term prognosis of ACLF to provide future directions for more dynamic prospective large-scale multicenter studies and a basis for individualized and precise treatment for ACLF patients. We searched PubMed and Web of Science with the term 'acute on chronic liver failure' and 'prognosis.' There was no date or language restriction, and our final search was on 26 October 2022.EXPERT OPINION:ACLF is a dynamic process, and the best prognostic marker is the clinical evolution of organ failure over time. New prognostic markers are developing not only in the fields of genetics and histology but also toward diversification combined with imaging. Determining which patients will benefit from continued advanced life support is a formidable challenge, and accurate short-term prognostic assessments of ACLF are a good approach to addressing this issue.

The phenotype shift in regulatory T cells (Tregs) contributes to immunopathogenesis of autoimmune diseases. The current study was aimed to investigate the regulatory function of interleukin-35 (IL-35) to T helper 22 (Th22) cell phenotype shift in Tregs in primary biliary cholangitis (PBC). Fifty-five PBC patients and twenty-four controls were enrolled. CD4+CD25+CD127dim/- Tregs and Th22 cells were investigated by flow cytometry. Forkhead box P3 (FoxP3) and aryl hydrocarbon receptor (AhR) mRNA levels were assessed by real-time polymerase chain reaction. Plasma IL-10 and IL-22 levels were measured by ELISA. Purified Tregs were stimulated with exogenous IL-35, and were co-cultured with autologous CD4+CD25- T cells. Cellular proliferation and cytokine production was measured. Purified Tregs were also cultured into Th22 condition in the presence or absence of exogenous IL-35, and Th22 phenotype were assessed. PBC patients had lower levels of Treg percentage, FoxP3 mRNA, and plasma IL-10, while had higher levels of Th22 proportion, AhR mRNA, and plasma IL-22. Tregs from PBC patients showed reduced immunosuppressive activity, which presented as increased cellular proliferation, interferon-γ production and decreased IL-35/IL-10 secretion in co-culture system. Tregs shifted into Th22 phenotype in PBC patients with elevated CCR4, CCR6, and CCR10 expression as well as increased IL-22 production. IL-35 not only enhanced inhibitory function of Tregs but also suppressed phenotype shift of Tregs into Th22 phenotype in PBC patients. This process was accompanied by elevation of IL-10 and transforming growth factor-β1 secretion by Tregs from PBC patients. The present data suggested that reduced IL-35 might be insufficient to maintain Tregs function and phenotype shift from Tregs into Th22 phenotype in PBC patients.

Interleukin 35 (IL-35) mediates immunosuppression of T cells in autoimmune diseases. T cells play an important role in primary biliary cholangitis (PBC) with incompletely elucidated pathogenesis. Thus, we aimed to investigate the role of IL-35 regulation on T cells in PBC patients. Fifty-one PBC patients and 28 controls were enrolled in this study. Plasma IL-35 level was measured. Purified peripheral CD4+ and CD8+ T cells were stimulated with exogenous IL-35 to investigate their functional phenotypes. IL-35-treated CD8+ T cells were cultured with human intrahepatic biliary epithelial cell line to determine the cytotoxicity of CD8+ T cells from PBC patients. Plasma IL-35 concentration was lower in PBC patients and negatively correlated with alkaline phosphatase. CD4+ T cells from PBC patients exhibited elevated transcription factor expressions and cytokine secretion, whereas CD8+ T cells produced increased cytotoxic molecules and cytokines. In vitro IL-35 stimulation suppressed the production of IL-17 and IL-22 by CD4+ T cells from PBC patients. CD8+ T cells treated with IL-35 mediated reduced target cell death in the direct contact co-culture system in PBC patients. This process was accompanied by reduced production of cytotoxic molecules and cytokines and increased expressions of immune checkpoint receptors in CD8+ T cells. Reduced circulating IL-35 might be insufficient to suppress T cell function, leading to the immune dysregulation in PBC patients.

Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a group of syndromes in which multiple pathogenic factors lead to the proliferation of activated lymphocytes and histiocytes that secrete large amounts of inflammatory cytokines[[1]](#ref-0001).HLH is a multi-organ hyperinflammatory syndrome caused by the secretion of large amounts of inflammatory cytokines from