Acute liver failure (ALF) is a life-threatening condition characterized by massive hepatocyte death, inflammation, and poor prognosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) have shown promise in tissue repair, but their therapeutic role and mechanisms in ALF remain unclear. MSC-sEVs were isolated, characterized, and administered to LPS/D-GalN-induced ALF mice and H2O2-injured hepatocytes. NEMO expression was modulated in vitro and in vivo to assess its role in MSC-sEV-mediated hepatoprotection. MSC-sEVs significantly improved liver histology, reduced serum ALT/AST levels, and enhanced survival in ALF mice. Transcriptomic profiling revealed that MSC-sEVs restored the expression of NEMO, a critical regulator of TNF/NF-κB signaling, which was otherwise downregulated in ALF livers. Mechanistically, MSC-sEVs enhanced NEMO expression, activated TNF/NF-κB signaling (as evidenced by upregulated IκB phosphorylation and NF-κB (p65) nuclear translocation), increased c-FLIP levels, and suppressed cleaved caspase-3, leading to reduced inflammation and apoptosis both in vivo and in vitro. Overexpression of NEMO promoted hepatocyte survival, while its knockdown reversed the protective effects of MSC-sEVs, confirming a NEMO-dependent mechanism. MSC-sEVs exert potent hepatoprotective and anti-inflammatory effects in ALF through NEMO-dependent activation of TNF/NF-κB signaling, highlighting their potential as a cell-free therapeutic strategy for ALF.

Background:Clonorchiasis frequently presents as intrahepatic space-occupying lesions, posing a diagnostic challenge due to the low sensitivity of fecal examination. While Praziquantel is the standard first-line therapy, Albendazole is often used empirically in suspected cases. However, the comparative efficacy of these two agents across different levels of diagnostic certainty (confirmed vs. suspected) remains poorly defined. Methods:This retrospective cohort study included 151 patients with clonorchiasis-related hepatic lesions treated at our institution between January 2018 and December 2025. Patients were categorized into a Praziquantel group (n = 78) and an Albendazole group (n = 73). The primary outcome was clinical cure within 90 days, defined as symptom resolution, lesion reduction ≥50%, and normalization of eosinophil counts. Multivariable logistic regression and Generalized Estimating Equations (GEE) were employed to evaluate the interaction between treatment regimens and diagnostic certainty. Results:The overall clinical cure rate was higher in the Praziquantel group (76.9%, 60/78) than in the Albendazole group (67.1%, 49/73), though the difference was not statistically significant (χ 2 = 1.804, P = 0.179). Stratified analysis revealed that Praziquantel was significantly more effective in confirmed cases (90.0% vs. 62.5%, P = 0.047), whereas no significant difference was observed in suspected cases (68.8% vs. 68.4%, P = 0.971). The "Drug/times Diagnosis" interaction test showed marginal significance (P = 0.064). After adjusting for confounders, Albendazole showed similar clinical outcomes to Praziquantel (Adjusted OR = 0.665, 95% CI: 0.298-1.482, P = 0.318). GEE analysis confirmed a significant "Drug × Time" interaction (P < 0.001), indicating distinct kinetic patterns of recovery, with Praziquantel demonstrating a superior cure advantage over time. Age was identified as an independent predictor of clinical cure (P = 0.017). Conclusion:The efficacy of Albendazole in treating clonorchiasis-related hepatic lesions is modulated by diagnostic certainty. While Praziquantel remains the superior choice for confirmed cases, Albendazole demonstrates comparable clinical efficacy in stool-negative suspected cases. These findings indicate that Albendazole demonstrates similar lesion resolution to Praziquantel in stool-negative suspected cases. However, given the retrospective design, these results should be interpreted as hypothesis-generating, necessitating prospective trials for confirmation.

BACKGROUND:Thymosin α1 (Tα1) has been shown to improve survival in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), but its immunomodulatory mechanisms remain unclear. This study investigated how Tα1 restores immune homeostasis to confer a survival benefit in these patients. METHODS:In this open-label, randomized controlled trial (NCT03082885), 73 patients with HBV-ACLF received either standard medical therapy (SMT, n = 38) or SMT plus Tα1 (n = 35). Peripheral blood immune cell subsets were analyzed by flow cytometry and serum cytokine levels were measured by ELISA. Patients were stratified by 90-day transplant-free survival. RESULTS:Patients who survived at 90 days exhibited a higher proportion of effector T (TE) cells and lower levels of regulatory T cells (Tregs) at baseline compared to non-survivors. Survivors also had significantly higher initial levels of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and lower levels of TGF-β. Over time, survivors showed a gradual decline in inflammatory markers, whereas non-survivors developed a progressive inflammatory storm. Tα1 treatment significantly increased 90-day transplant-free survival and was associated with reduced frequencies of Tregs and CD226low/- Treg subsets at weeks 4-8. Tα1 also moderated the late-stage hyperinflammatory response without compromising early immune activation. CONCLUSIONS:Tα1 improves clinical outcomes in HBV-ACLF by rebalancing the immune response-mitigating excessive inflammation and preventing immune paralysis by modulating T-cell differentiation and cytokine production, thereby breaking the cycle of hyperinflammation and immunosuppression that characterizes ACLF progression.

Macrophages related inflammation plays a pivotal role in the progression of acute-on-chronic liver failure (ACLF). Our previous study has found that mesenchymal stem cells (MSCs) alleviate inflammatory damage in ACLF mice by promoting polarization of M2 macrophages through upregulating the expression of Mer tyrosine kinase (MERTK). In this study, we investigate the specific mechanism by which MSCs regulate MERTK. Bioinformatics was used to predicted the candidate transcription factors for Mertk gene and FOS like antigen 1(FOSL1) was chosen. After overexpressing or knocking down Fosl1, MERTK, iNOS and Arg-1 were analyzed in Raw264.7 and/or J774a.1 cells. Conditioned medium (CM) of MSCs was cocultured with macrophages and the expressions of TGF-β1 and FOSL1 were detected. Male Balb/c mice aged 5–6 weeks were used to establish ACLF mice model. And adeno-associated virus or MSCs-CM was injected through tail vein. Then mouse liver tissue was collected and analyzed. FOSL1 promotes M2 polarization of macrophages by upregulating the expression of MERTK in vivo and in vitro. The luciferase reporter assays indicate that FOSL1 acts as a transcription factor of Mertk gene. Furthermore, MSCs-CM promotes expression of FOSL1 and M2 polarization of macrophages through TGF-β1 receptor. After knocking down TGF-β1 in MSCs using shRNA, shRNA-CM could not upregulate the expression of FOSL1, and promote M2 polarization of macrophages as CM does. Our findings show that TGF-β1 secreted by MSCs promotes M2 macrophages polarization via FOSL1/MERTK axis in ACLF mice, providing a novel therapeutic target for ACLF treatment.

BACKGROUND:Constipation is common in patients with acute ischemic stroke, yet its incidence and prognosis remain unknown. Herein, we investigate the incidence of new-onset constipation and its risk factors and relationship with stroke severity and prognosis. METHODS:This prospective study enrolled 358 patients diagnosed with acute ischemic stroke. The Constipation Scoring System was used to assess new-onset constipation during hospitalization. Demographics, medical histories, clinical data, laboratory parameters, and medication use were compared between non-constipation and constipation groups. Univariate and multivariate logistic regression and multiple linear regression were used to explore potential influencing factors and prognosis. RESULTS:The cumulative incidence of new-onset constipation during was 41.6 %. Its occurrence was closely associated with multiple demographic factors and laboratory markers. Binary logistic regression identified age (P = 0.002), eosinophil count (P = 0.004), and modified Rankin scale (mRS) scores at admission (P = 0.048) as significant predictors. The NIHSS (β = 0.179, P = 0.001) and mRS (β = 0.168, P = 0.016) scores at admission significantly positively predicted the Constipation Assessment Scale. NIHSS scores at admission (β = 0.300, P < 0.001) also positively predicted constipation severity at six-month follow-up. CONCLUSION:New-onset constipation is a common complication of acute ischemic stroke hospitalization. NIHSS, mRS, and water swallowing test scores at admission can predict the incidence and severity of constipation during hospitalization and at the 6-month follow-up. These findings provide clinical insights for early risk assessment and intervention to mitigate constipation-related complications in patients with stroke.

BACKGROUND:Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear. METHODS:The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential. RESULTS:Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes. CONCLUSION:MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy.

Digital therapeutics have developed rapidly in recent years, providing a new method for disease management. The burden of liver diseases in China is heavy, and there are obvious problems in disease management. This paper expounds on the definition and classification of digital therapeutics, introduces their application in liver disease treatment and management in detail, and analyzes their development prospects in the field of liver diseases and future challenges.Graphical abstract available for this article.

Since July 2025, Foshan has experienced the largest outbreak of Chikungunya fever in China. This single-centre retrospective study included 1,908 laboratory-confirmed cases. Phylogenetic analysis identified the East/Central/South African lineage, closely related to the 2025 La Réunion strain. The included cases were all non-severe, showed no sex bias, but exhibited clear regional clustering. Fever (86.8%), arthralgia (85.4%), and rash (64.1%) were predominant symptoms. Fever and rash were more common in minors, while arthralgia increased with age. Lymphopenia occurred in 65.5% of patients and was more common in elderly patients, who had higher viral loads and longer RNA clearance times. Age, sex and viral load independently influenced clinical manifestations and laboratory characteristics. The findings provide initial descriptive evidence and highlight age-related differences in chikungunya’s clinical and virological profiles. Long-term follow-up and larger-scale investigations were necessary to provide evidence for clinical decision-making.

As immunotherapy gains increasing attention and clinical application, the immune modulation therapy has been widely used in the treatment of infectious and critical diseases. Clinical evidence has been accumulated for application of thymosin alpha 1 (T alpha 1), a classical immune modulator, in related domains. The National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases and other institutions invited multidisciplinary experts to develop this expert consensus on clinical application of T alpha 1 in infectious diseases and critical care medicine. Based on the latest domestic and international research findings and considering relevant factors, including economics, patient preferences and values, tradeoffs, accessibility, fairness and acceptability, the consensus assesses the quality levels of current evidence and forms 10 recommendations on the application of T alpha 1 in treatment of liver diseases, viral infections, bacterial infections and critical illnesses. This consensus aims to enhance understanding of T alpha 1 and improving its standardized application for clinicians.

BackgroundThe correlation between metabolic syndrome (MetS) and hepatitis B surface antigen (HBsAg) loss remains to be further elucidated, particularly in patients receiving pegylated interferon-α (PEG-IFN) treatment.Methods758 patients with low HBsAg quantification who had received nucleos(t)ide analog (NUC) therapy for at least one year and subsequently switched to or add on PEG-IFN therapy over an unfixed course were enrolled. 412 patients were obtained with baseline data matched. A total of 206 patients achieved HBsAg loss (cured group) within 48 weeks. Demographic and biochemical data associated with MetS were gathered for analysis. HepG2.2.15 cell line was used in vitro experiments to validate the efficacy of interferon-α (IFN-α).ResultsThe proportion of patients with diabetes or hypertension in the uncured group was significantly higher than in the cured group. The levels of fasting blood glucose (FBG) and glycated albumin remained elevated in the uncured group over the 48 weeks. In contrast, the levels of blood lipids and uric acid remained higher in the cured group within 48 weeks. Triglycerides levels and liver steatosis of all patients increased after PEG-IFN therapy. Baseline elevated uric acid levels and hepatic steatosis may be beneficial for HBsAg loss. IFN-α could induce hepatic steatosis and indirectly promote HBsAg loss by increasing triglyceride level through upregulation of acyl-CoA synthetase long-chain family member 1(ACSL1).ConclusionsIFN-α could induce liver steatosis to promote HBsAg loss by increasing triglyceride level through upregulation of ACSL1. Comorbid diabetes may be detrimental to obtaining HBsAg loss with PEG-IFN therapy in CHB patients.

Abstract Background Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. Results Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. Conclusion Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF. Graphical Abstract

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-alpha (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-gamma(+) Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-gamma) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86(+) M1 and CD206(+) M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-gamma(+) Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

End-stage liver disease (ESLD) includes decompensated liver cirrhosis and liver failure, which usually have dangerous conditions and a poor prognosis. Liver transplantation is the only effective therapy for ESLD, but its clinical application is limited due to shortage of liver donors, immunological rejection, and expensive costs. Mesenchymal stem cells (MSCs) can differentiate into hepatocyte-like cells and alleviate liver fibrosis by regulating immune function through paracrine, and therefore, MSCs have a wide application prospect in the field of ESLD treatment. A number of clinical studies have shown that MSC infusion is safe and effective in the treatment of ESLD during a short period of time, and there is also certain clinical evidence for its long-term safety and efficacy. MSC-derived exosomes (MSC-Exo) do not have a complete cellular structure and can promote hepatocyte regeneration through a variety of mechanisms, and their clinical value has attracted more and more attention, but there are few studies on this issue. Currently, the core mechanism of MSC therapy for ESLD and the standardized process of MSC preparation are the problems needing to be solved urgently.

Balancing hepatocyte death and proliferation is key to non-transplantation treatments for acute liver failure (ALF), which has a high short-term mortality rate. Small extracellular vesicles (sEVs) may act as mediators in the repair of damaged liver tissue by mesenchymal stem cells (MSCs). We aimed to investigate the efficacy of human bone marrow MSC-derived sEVs (BMSC-sEVs) in treating mice with ALF and the molecular mechanisms involved in regulating hepatocyte proliferation and apoptosis. Small EVs and sEV-free BMSC concentrated medium were injected into mice with LPS/D-GalN-induced ALF to assess survival, changes in serology, liver pathology, and apoptosis and proliferation in different phases. The results were further verified in vitro in L-02 cells with hydrogen peroxide injury. BMSC-sEV-treated mice with ALF had higher 24 h survival rates and more significant reductions in liver injury than mice treated with sEV-free concentrated medium. BMSC-sEVs reduced hepatocyte apoptosis and promoted cell proliferation by upregulating miR-20a-5p, which targeted the PTEN/AKT signaling pathway. Additionally, BMSC-sEVs upregulated the mir-20a precursor in hepatocytes. The application of BMSC-sEVs showed a positive impact by preventing the development of ALF, and may serve as a promising strategy for promoting ALF liver regeneration. miR-20a-5p plays an important role in liver protection from ALF by BMSC-sEVs.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Abstract Background Thyroid dysfunction has been reported in severe liver diseases. The aim of this study was to analyze the impact of serum thyroid-stimulation hormone (TSH) levels on the prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). Methods This retrospective cohort study included 1,862 patients with HBV-related ACLF. Risk factors associated with 30-day and 90-day survival, hazard ratios (HRs), and 95% confidence intervals (CIs) for TSH were estimated using Cox proportional hazards regression. The Area Under the ROC curve (AUROC) analysis was carried out, and the cut-off values were calculated. After grouping by the cut-off value, survival was compared between the groups using the log-rank test. This study data is from the “Survival Cohort Study (SCS)”, which has been registered at ClinicalTrials.gov (NCT03992898). Results Multivariate analysis indicated that an elevated TSH level was a highly significant predictor for 30-day survival (HR = 0.743, 95% CI: 0.629–0.878, P < 0.001) and 90-day survival (HR = 0.807, 95% CI: 0.717–0.909, P < 0.001). The AUROC of TSH level for 30-day and 90-day mortality were 0.655 and 0.620, respectively, with the same best cut-off values of 0.261 µIU/mL. Log-rank test showed that the group with higher TSH level had higher 30-day (78.5%, 95% CI: 76.1%-80.9% vs. 56.9%, 95% CI: 53.4%-60.4%; P < 0.001) and 90-day survival rate (61.5%, 95% CI: 58.6%-64.4% vs. 42.8%, 95% CI: 39.3%-46.3%; P < 0.001). Similar findings were observed in subgroups analysis. After adjusting for age and other risk factors, the higher level of TSH remained associated with 30-day survival (HR = 0.602, 95% CI: 0.502–0.721, P < 0.001) and 90-day survival (HR = 0.704, 95% CI, 0.609–0.814, P < 0.001). Conclusions Serum TSH level significantly correlate with HBV-related ACLF patients’ survival and may be of value for predicting 30-day and 90-day survival of patients with HBV-related ACLF.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe and life-threatening complication, characterised by multi-organ failure and high short-term mortality. However, there is limited information on the impact of various comorbidities on HBV-ACLF in a large population. This study aimed to investigate the relationship between comorbidities, complications and mortality. In this retrospective observational study, we identified 2166 cases of HBV-ACLF hospitalised from January 2010 to March 2018. Demographic data from the patients, medical history, treatment, laboratory indices, comorbidities and complications were collected. The mortality rate in our study group was 47.37%. Type 2 diabetes mellitus was the most common comorbidity, followed by alcoholic liver disease. Spontaneous bacterial peritonitis, pneumonia and hepatic encephalopathy (HE) were common in these patients. Diabetes mellitus and hyperthyroidism are risk factors for death within 90 days, together with gastrointestinal bleeding and HE at admission, HE and hepatorenal syndrome during hospitalisation. Knowledge of risk factors can help identify HBV-ACLF patients with a poor prognosis for HBV-ACLF with comorbidities and complications.