IntroductionInfection is a major complication of liver cirrhosis and is associated with substantial morbidity and mortality. However, regional data on pathogen distribution, antimicrobial resistance patterns, and gut microbiota and metabolic alterations among cirrhotic patients with infection in Northwest China remain limited. This study aimed to characterize these features and explore the associations between gut microbiota, short-chain fatty acids (SCFAs), and clinical inflammatory indices in cirrhotic patients with infection.MethodsWe retrospectively analyzed 4,425 hospitalized patients with liver cirrhosis between January 2017 and October 2025, including 1,056 patients with concurrent infections, to characterize pathogen distribution and antimicrobial susceptibility patterns. In addition, a prospectively enrolled subgroup of 86 participants was analyzed for gut microbiota composition and fecal SCFA levels. Gut microbiota was characterized using 16S rRNA gene sequencing, and fecal SCFA concentrations were determined by appropriate analytical methods. The discriminatory ability of inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII), was assessed using receiver operating characteristic (ROC) curve analysis.ResultsThe most frequently isolated Gram-negative bacteria were Escherichia coli (22.32%), Klebsiella pneumoniae (13.27%), Acinetobacter baumannii (7.36%), and Pseudomonas aeruginosa (5.07%), while the predominant Gram-positive bacteria were Enterococcus faecium (9.17%) and Staphylococcus aureus (6.39%). Fungi accounted for 4.58% of isolates. Antimicrobial susceptibility testing revealed substantial resistance to multiple antibiotics among the major pathogens. ROC analysis showed that NLR and MLR had high discriminative ability for distinguishing infected from non-infected cirrhotic patients, with AUCs of 0.9447 and 0.9083, respectively, while SII showed comparatively lower discriminative ability. In the microbiome subgroup, patients with spontaneous bacterial peritonitis (LCIF-SBP) exhibited distinct gut microbiota profiles compared with cirrhotic patients without infection (LCNOIF) and healthy controls. SCFA-producing genera, including Bifidobacterium and Faecalibacterium, were reduced, whereas Escherichia-Shigella was enriched. Fecal butyrate levels were significantly lower in the LCIF-SBP group than in the LCNOIF group. Correlation analysis showed that Escherichia-Shigella was negatively correlated with fecal butyrate levels and positively correlated with MLR.DiscussionOur findings provide regional data on pathogen distribution, antimicrobial resistance, gut microbiota alterations, and SCFA profiles among cirrhotic patients with infection in Northwest China. The observed associations between gut microbial dysbiosis, reduced butyrate levels, and inflammatory indices highlight potential links between intestinal microbial alterations and infection in cirrhosis. Further longitudinal, multicenter, and mechanistic studies are needed to determine whether these microbiota and metabolic alterations contribute causally to infection susceptibility and to evaluate their potential clinical relevance.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). It is characterized by autoantibody deposition and immune complex formation within the kidney, leading to progressive nephron loss and end‑stage renal disease. Suppression of immunology is a cornerstone for managing LN. The present study identified withaferin A (WA) as a promising therapeutic candidate for SLE via connectivity map analysis and validated its efficacy in ameliorating LN in an MRL/lpr mouse model. Candidate drugs for LN were identified via the Connectivity Map database by integrating transcriptomic signatures from GSE135779, GSE162577 and GSE142016. An animal model was established to evaluate the therapeutic efficacy of WA on LN‑associated inflammation and splenic dysfunction, followed by RNA‑sequencing analysis. To elucidate the mechanistic role of PON1 in WA‑mediated protection, siRNA‑mediated knockdown and plasmid‑driven overexpression were performed in HK‑2 cells. Furthermore, the direct impact of WA was assessed using isolated primary B cells. WA improved renal function by mitigating splenic immune cell dysregulation and attenuating renal inflammation. Mechanistically, RNA‑sequencing analysis and functional validation revealed that WA upregulated paraoxonase 1 (Pon1) expression, which in turn alleviates renal injury by decreasing reactive oxygen species via the peroxisome proliferator‑activated receptor signaling pathway. Pon1 activation enhanced cell viability, suppressed inflammatory responses and decreased oxidative stress in HK‑2 cells, underscoring its potential as a novel therapeutic target for LN. Collectively, the findings demonstrate WA is a viable candidate for SLE/LN treatment and Pon1 is a pivotal mediator of its protective effects, thereby providing a dual‑strategy insight for clinical intervention.

BACKGROUND & AIMS:Patients with chronic hepatitis B (CHB) with low hepatitis B surface antigen (HBsAg) levels and suppressed hepatitis B virus (HBV) DNA on nucleos(t)ide analogues (NAs) may achieve functional cure with peginterferon α (PegIFNα)-based therapy. This real-world multicenter study (Everest Project) in China aimed to evaluate the effectiveness and safety of PegIFNα-2b and determine the predictors of HBsAg loss. METHODS:Patients with NA-suppressed CHB who were hepatitis B e antigen (HBeAg)-negative, had HBsAg ≤1500 IU/mL, and undetectable HBV DNA, were administered PegIFNα-2b for 48 weeks, either as a switch-to or add-on therapy. The primary endpoint was HBsAg loss at week 48. RESULTS:Among 15,896 patients in the full analysis set (FAS) and 12,260 in the per-protocol set (PPS), HBsAg loss rate at week 48 was 26.4% and 33.8%, respectively, after propensity score weighting, with no significant difference between switch-to and add-on groups. Key predictors of HBsAg loss included lower baseline HBsAg and HBsAg decline >63.3% at week 12 and >95.3% at week 24. Among patients who underwent >24 weeks of post-treatment follow-up, HBsAg loss rates at week 24 were 28.7% and 35.6% in the FAS and PPS, respectively. Of those who received consolidation therapy, 85.9% maintained HBsAg loss at week 72. Adverse event-related discontinuation occurred in 5.6% and 4.4% of those in the FAS and PPS, respectively. CONCLUSIONS:PegIFNα-2b enhances HBsAg loss in patients with NA-suppressed, HBeAg-negative CHB with low HBsAg levels. Baseline and on-treatment predictors support the achievement of a functional cure. CLINICALTRIALS:gov, Number: NCT04035837.

BACKGROUND & AIM:M2 macrophages are key drivers of immune-mediated liver injury. The aim of this study was to investigate the mechanisms by which Annexin A5 regulates ferroptosis in M2 macrophages and its protective effect against immune liver injury. METHODS:The colocalization of ferroptosis in M2 macrophages from autoimmune hepatitis (AIH) patients and mice with ConA-induced immune liver injury was analyzed via laser confocal microscopy. The effects of ferritinophagy and autophagosomal-lysosomal fusion on the regulation of ferroptosis in M2 macrophages by Annexin A5 were investigated through mCherryGFP-LC3B adenovirus transfection. Ferroptosis of M2 macrophages was studied by using si-RNA and chemical inhibitors and agonist of nuclear factor erythroid 2-related factor 2 (NRF2) and extracellular signal-regulated kinase (ERK). Bone marrow-derived macrophages were polarized into M2 macrophages for use in cell transfer experiments. A coculture model of M2 macrophages and hepatocytes was established to study the effect of M2 macrophages on liver regeneration. RESULTS:M2 macrophages are highly sensitive to ferroptosis in immune-mediated liver injury, and Annexin A5 can effectively inhibit ferroptosis in M2 macrophages, thereby exerting a protective effect on immune-mediated liver injury. Annexin A5 alleviates ferritinophagy by inhibiting the degradation of NRF2 and the phosphorylation of ERK1/2, as well as by inhibiting autophagosome-lysosome fusion. This enhances the resistance of M2 macrophages to ferroptosis and improves outcomes in immune-related liver injury. Additionally, the inhibition of ferroptosis in M2 macrophages promotes hepatocyte regeneration. CONCLUSION:Our findings comprehensively reveal that the modulation of the NRF2-ERK1/2 signaling pathway by Annexin A5 is essential for mitigating ferroptosis in M2 macrophages during immune-mediated liver injury. Therefore, targeting Annexin A5 may offer novel therapeutic approaches for the treatment of immune-mediated liver injury.

Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver injury of unknown etiology. The onset of this disease involves the activation and recruitment of diverse immune and non-immune cells, which in turn trigger hepatic damage. Immune checkpoint molecules (ICM) are expressed on the surface of multiple cell types. By regulating cellular functional states, they help limit the intensity and duration of immune responses, thereby preventing excessive inflammation and tissue damage, and maintaining immune homeostasis. In AIH, however, this natural "braking" mechanism is impaired, leading to aberrant activation of both immune and non-immune cells and the breakdown of immune homeostasis. Consequently, ICM are likely to play a critical role in the pathogenesis of AIH. A deeper understanding of the function of ICM in AIH not onlyadvances our insight into the disease mechanism, but also suggests that targeting these molecules may represent a promising therapeutic strategy for the treatment of AIH.

Cirrhosis, characterized by extensive liver fibrosis and architectural distortion, is commonly associated with coagulation disorders that increase the risk of both bleeding and thrombosis. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for liver diseases, including cirrhosis, due to their regenerative and immunomodulatory properties. This review delves into the intricate relationship between MSCs and the coagulation system in cirrhotic patients, examining the impact on platelet dysfunction, coagulation factor synthesis, endothelial dysfunction, and fibrinolysis. The review highlights MSCs’ multilineage differentiation potential and their ability to secrete both pro- and anti-coagulant factors, which are crucial in the context of liver disease. Clinical and preclinical findings on the effects of MSC therapy on coagulation are reviewed, along with safety and risk assessments. This review highlights the promising potential of MSCs in alleviating cirrhosis-associated coagulopathy, while identifying key challenges that must be addressed to advance clinical translation. Further research is therefore warranted to elucidate the underlying mechanisms and to optimize therapeutic strategies for clinical application.

Immune-mediated liver injury (ILI) is a condition characterized by inflammation and cell death in the liver. Disulfiram, an FDA-approved drug for alcohol aversion, shows potential as a therapeutic agent in liver diseases, although its effects on immune liver injury remain unclear. This study aims to investigate the therapeutic effects of disulfiram using a mouse model of ILI induced by concanavalin A (ConA) and AML12 hepatocytes in vitro. Various techniques were employed, including Western blotting, qRT-PCR, cell viability assays, histopathological evaluations, immunohistochemistry, TUNEL staining, caspase-1 activity assays, cytokine detection, Cellular Thermal Shift Assay, and EdU proliferation assays. The results demonstrate that the ConA-induced ILI model exhibits significant liver damage and cellular pyroptosis, with disulfiram administered at specific concentrations markedly reducing the inflammatory response. Moreover, disulfiram attenuates pyroptosis in ConA-induced ILI and reduces cell injury in AML12 hepatocytes triggered by ConA and LPS + ATP, while facilitating post-injury cell proliferation. Mechanistically, the anti-pyroptosis effects of disulfiram are associated with the inhibition of the NF-κB signaling pathway in vitro. These results suggest that hepatocellular pyroptosis plays a pivotal role in the pathogenesis of ILI, and that disulfiram alleviates ILI symptoms by modulating the NLRP3/Caspase-1/GSDMD-mediated classical pyroptosis pathway through the NF-κB signaling cascade. Subsequent investigations will explore the impact of disulfiram in diverse liver injury models and its synergistic effects with other drugs to improve therapeutic outcomes. Additionally, clinical trials are imperative to validate these findings in humans and establish disulfiram as a standard treatment for ILI, thereby paving the way for innovative therapeutic approaches.

BACKGROUND:Ferroptosis is a regulated, iron-dependent form of cell death triggered by toxic accumulation of lipid peroxides on cell membranes. Although it is established that glycosphingoid metabolites can activate the ferroptosis signaling pathway, whether they are involved in regulating endoplasmic reticulum stress (ERS)-ferroptosis in immune-mediated liver injury requires further investigation. METHODS:This study used the GCS inhibitor GENZ-123346 (GENZ) to treat ConA-induced immune liver injury in mice. Inflammatory factor levels and liver histology were analyzed to evaluate GENZ's effects. Additionally, the antioxidant and lipid peroxidation capacity of GENZ was tested in vivo and in vitro. Based on the regulation of NFE2-related factor 2 (NRF2) signaling pathway expression (including si-NRF2, NRF2 inducer sulforaphane (SFN), and inhibitor ML385), the regulatory effect of GENZ on ERS-ferroptosis was investigated. RESULTS:GENZ administration improved the survival rate of mice with immune-mediated liver injury, decreased serum transaminase activity, inhibited inflammatory factor production, reduced hepatocyte ferroptosis. In in vitro experiments, ferroptosis in AML12 cells was accompanied by the activation of ERS-related proteins Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and mild alterations in endoplasmic reticulum ultrastructure. Inhibition of ERS by 4-phenylbutyric acid (4-PBA) attenuated ferroptosis in AML12 cells. However, when the cells were treated with the ferroptosis inducer RSL3 in combination with the ERS inducer thapsigargin (Tg), GENZ could not effectively suppress ferroptosis. Silencing NRF2 exacerbated cellular ferroptosis and ERS while diminishing the expression of downstream effectors heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Conversely, SFN treatment alleviated these effects and upregulated NRF2 signaling, increasing HO-1 and NQO1 expression. Furthermore, ML385 administration reversed the hepatoprotective and antioxidant effects of GENZ on immune-mediated liver injury in mice. CONCLUSIONS:GCS inhibition exerts hepatoprotective effects by modulating the NRF2 antioxidant pathway to suppress ERS and hepatocyte ferroptosis, revealing a novel role of glycosphingolipid metabolism in immune-mediated liver injury and programmed hepatocyte death.

BACKGROUND Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC. AIM To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC. METHODS The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro , and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo . RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF , MMP9 , and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model. CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo .

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/).

The annexin superfamily proteins, a family of calcium-dependent phospholipid-binding proteins, are involved in a variety of Ca²+-regulated membrane events. Annexin A, expressed in vertebrates, has been implicated in a variety of regulated cell death (RCD) pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and neutrophil extracellular trap-induced cell death (NETosis). Given that inflammation is a key driver of cell death, the roles of Annexin A in inflammation have been extensively studied. In this review, we discuss the regulatory roles of Annexin A in RCD and inflammation, the development of related targeted therapies in translational medicine, and the application of animal models to study these processes. We also analyze current challenges and discuss future directions for improved diagnostic and therapeutic strategies.

PANoptosis is a multimodal form of cell death that involves inflammatory, apoptotic, and necroptotic pathways, playing a key role in the development of liver diseases. This article first outlines the definition and characteristics of PANoptosis, and then explores its mechanisms of action in different types of liver diseases, including acute liver injury, liver failure, metabolic dysfunction-associated fatty liver disease, and hepatocellular carcinoma. Furthermore, this article analyses the molecular regulatory network of PANoptosis and potential therapeutic targets. Finally, this article summarises the current research on PANoptosis in liver diseases and future research directions, and it reviews the role of the emerging cell death mechanism of PANoptosis in liver diseases.

Objectives: Liver fibrosis staging and etiology diagnosis are critical for patient management, but non-invasive methods remain challenging. This study aims to evaluate the performance of radiomics models using 2D shear wave elastography (2D-SWE) of the liver and spleen for liver fibrosis staging and etiology differentiation, comparing them with serum biomarkers and conventional ultrasound. Methods: A retrospective analysis was conducted on 198 patients with liver fibrosis confirmed by biopsy. Radiomics features were extracted from the liver and spleen grayscale and 2D-SWE images. Machine learning (ML) and transfer learning (TL) models were established for fibrosis staging and etiology diagnosis. Model performance was evaluated according to receiver operating characteristic (ROC) curves. Results: For fibrosis staging, 2D-SWE-based models outperformed grayscale and serum biomarkers. The combined liver–spleen TL model achieved exceptional validation performance (AUCs 0.99 for S4, 0.98 for ≥S3, 1.00 for ≥S2). For etiology diagnosis, the liver 2D-SWE TL model and the combined liver–spleen TL model achieved AUCs of 0.97 and 0.94, respectively, significantly outperforming ML models in terms of AUC. Conclusions: Integrating liver and spleen 2D-SWE radiomics with TL significantly improves non-invasive liver fibrosis staging and etiology diagnosis, offering superior accuracy over conventional methods. This approach holds promise for clinical application, though further validation is needed.

Streptococcus constellatus, recognized as a commensal bacterium, has the potential to induce severe infections in patients with immunodeficiency. Here, we reported a rare case of Streptococcus constellatus infection that manifested as gelatinous pleural effusion in a patient with HIV. Although the effusion was gelatinous and partially encapsulated, it was completely resolved with timely administration of antibiotics, thereby eliminating the necessity for thoracic drainage, urokinase injection, or surgical intervention.

Objective:Comparative analysis of the mNUTRIC and NRS-2002 scores for evaluating nutritional risk and predicting clinical outcomes in end stage liver disease patients.Method:A retrospective cohort study method was used to screen 114 cases with end-stage liver disease admitted to the intensive care unit (ICU) of the First Hospital of Lanzhou University from December 1, 2016 to March 31, 2021 according to the inclusion and exclusion criteria. The patient's demographic data, blood routine, blood biochemical indexes, coagulation function indexes, arterial blood gas analysis and imaging examination data were collected. The mNUTRIC score, NRS-2002 score, sequential organ failure (SOFA) score, model for end-stage liver disease (MELD) score, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, Child-Pugh grade, and clinical outcomes at 28 and 90 days at 24 h post-ICU admission were collected. The differences in clinical indicators between the mNUTRIC high group (≥5 points) and the low group, and the NRS-2002 high group (≥3 points) and the low group were compared. Spearman correlation analysis was used to explore the correlation between the mNUTRIC score and NRS-2002 score, clinical indicators, and 28 and 90-day mortality rates. Multivariate logistic regression analysis was used to determine the risk factors associated with 28-day and 90-day mortality in patients. The value of mNUTRIC score and NRS-2002 score in assessing the clinical outcomes of patients with end-stage liver disease was explored by receiver operating characteristic (ROC) curve.Results:The clinical indicators related to nutritional status of patients were worse in the high-mNUTRIC group than those in the low-mNUTRIC group, and the 28-day and 90-day mortality rates were significantly higher than those in the low-mNUTRIC group [89.0%(65/73) vs. 29.2%(12/41), 97.2%(71/73) vs. 39.0%(16/41), P<0.001]. There was no statistically significant difference in the incidence rate of hepatic encephalopathy, esophageal variceal bleeding, and ascites between the high and low mNUTRIC group. The clinical indicators related to nutritional status were worse in the high-NRS-2002 group than those in the low-NRS-2002 group of patients, and the 28-day and 90-day mortality rates were significantly higher than those in the low-group [73.0%(73/100) vs. 4/14, 81.0%(81/100) vs. 6/14, P=0.008, 0.004]. The NRS-2002 high-score group did not differ significantly from the low-score group in terms of hepatic encephalopathy, esophagogastric variceal bleeding, or ascites prevalence. Patient's age, white blood cell count (WBC), urea nitrogen (BUN), creatinine (UREA), uric acid (UA), total cholesterol (TG), Child-Pugh, MELD, SOFA, APACHE Ⅱscores were significantly positively correlated with the mNUTRIC score. Conversely, albumin (Alb) and Glasgow Coma Scale (GCS) were significantly negatively correlated. Patient's age, WBC, CREA, BUN, UREA, UA, Child-Pugh, MELD, SOFA, APACHE Ⅱwere significantly positively correlated with the NRS-2002 score.Conversely, albumin (Alb) and Glasgow Coma Scale (GCS) were significantly negatively correlated ( P<0.05). The 28-day and 90-day mortality rates of patients increased with the increase in the mNUTRIC scores. The mNUTRIC score was an independent predictor of death within 28 and 90 days in patients with end-stage liver disease. The area under the curve (AUC) of mNUTRIC for predicting patient death at 28 days was 0.864 (95% CI: 0.794-0.934). The AUC of NRS-2002 for predicting patient death at 28 days was 0.683 (95% CI: 0.573-0.792). The AUC of the two indicators combined for predicting patient death at 28 days was 0.868 (95% CI: 0.799-0.936). The AUC of mNUTRIC for predicting patient death at 90 days was 0.915 (95% CI: 0.861-0.969). The AUC of NRS-2002 for predicting patient death at 90 days was 0.715 (95% CI: 0.599-0.832). The AUC of the two indicators combined for predicting patient death at 90 days was 0.922 (95% CI: 0.871-0.972). Conclusion:mNUTRIC score and NRS-2002 score can better evaluate the nutritional status in patients with end-stage liver disease. The mNUTRIC score is a good predictor of 28-day and 90-day mortality in patients with end-stage liver disease, and its application value efficacy is enhanced when combined with NRS-2002.

BACKGROUND:Immunotherapy combinations have revolutionised the therapeutic landscape of advanced hepatocellular carcinoma (HCC), but not all yield a significant overall survival benefit, underscoring the need for novel effective agents. Anlotinib plus penpulimab has demonstrated encouraging activity and safety in a phase 2 study. In this phase 3 trial, we aimed to assess whether the combination of anlotinib plus penpulimab improved survival versus sorafenib in patients with unresectable HCC. METHODS:APOLLO was a multicentre, open-label, parallel-controlled, randomised, phase 3 trial conducted at 79 centres in China. Patients aged 18-75 years with unresectable HCC, no previous systemic therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned (2:1) to anlotinib (10 mg orally once daily on days 1-14) plus penpulimab (200 mg intravenously on day 1), or sorafenib (400 mg orally twice daily) every 3 weeks. Randomisation was done centrally using block randomisation with a fixed block size of 3 and stratified by the presence of macrovascular invasion or extrahepatic metastasis, α-fetoprotein concentration, and ECOG performance status. Sex (male or female) and ethnicity (Chinese or other) were self-reported. The co-primary endpoints were progression-free survival assessed by masked independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of the study drug and had at least one recorded safety assessment. Final progression-free survival and second interim overall survival analyses are presented. This trial is registered at ClinicalTrials.gov, NCT04344158, and follow-up is ongoing. FINDINGS:From Aug 11, 2020, to June 20, 2023, 940 patients were screened for inclusion in the trial, 291 were excluded, and 649 were randomly assigned to an intervention (433 were assigned to the anlotinib plus penpulimab group and 216 were assigned to the sorafenib group. 551 (85%) of the 649 patients were male and 98 (15%) were female. All patients were Chinese with a median age of 57 years (IQR 50-65). For the final analysis of progression-free survival (June 5, 2023), 636 patients (424 patients in the anlotinib plus penpulimab group vs 212 patients in the sorafenib group) comprised the intention-to-treat population. For the second interim analysis of overall survival (Jan 29, 2024), 649 patients (433 vs 216) comprised the intention-to-treat population. Median follow-up was 6·2 months (IQR 5·5-7·5) for the anlotinib plus penpulimab group and 4·2 months (2·9-7·1) for the sorafenib group for final progression-free survival analysis, and 15·3 months (14·3-17·3) for the anlotinib plus penpulimab group and 14·5 months (11·5-17·0) for the sorafenib group for the second interim overall survival analysis. Median progression-free survival was significantly extended with anlotinib plus penpulimab versus sorafenib (6·9 months [95% CI 5·8-8·0] vs 2·8 months [2·7-4·1]; hazard ratio [HR] 0·52 [95% CI 0·41-0·66]; p<0·0001). Median overall survival was significantly prolonged with anlotinib plus penpulimab compared with sorafenib (16·5 months [95% CI 14·7-19·0] vs 13·2 months [9·7-16·9]; HR 0·69 [95% CI 0·55-0·87]; p=0·0014). The most common grade 3 or worse treatment-related adverse events were hypertension (75 [17%] patients in the anlotinib plus penpulimab group vs 22 [10%] in the sorafenib group) and decrease in platelet count (39 [9%] vs 13 [6%]). Treatment-related serious adverse events occurred in 90 (21%) and 19 (9%) patients in the respective groups; treatment-related deaths occurred in one (<1%) patient in the anlotinib plus penpulimab group (upper gastrointestinal haemorrhage) and two (1%) patients in the sorafenib group (hepatic failure and death of unknown cause). INTERPRETATION:Anlotinib plus penpulimab significantly improved progression-free survival and overall survival versus sorafenib in unresectable HCC and might be a new first-line option. These findings require verification in other regions of the world. FUNDING:Chia Tai Tianqing Pharmaceutical Group.

To identify early predictive factors for hepatitis B surface antigen (HBsAg) clearance at week 48 following pegylated interferon (Peg-IFN) therapy in inactive HBsAg carriers (IHC), and to develop an early machine learning-based model to assist clinical decision-making. This retrospective analysis was based on a multicenter, prospective cohort and included 777 IHC patients who received at least 48 weeks of Peg-IFN therapy. Least Absolute Shrinkage and Selection Operator (LASSO) regression and the Boruta algorithm were applied to select predictive variables. Nine machine learning models—including logistic regression (LR), decision tree (DT), and random forest (RF)—were constructed and evaluated using 10-fold cross-validation. An external validation cohort (n = 167) from three medical centers in Beijing was used for model validation. SHapley Additive exPlanations (SHAP) values were used to interpret variable contributions. The overall HBsAg clearance rate at week 48 was 29.9

BACKGROUND AND AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to severe forms such as metabolic dysfunction-associated steatohepatitis (MASH). Effective treatments for MASH are urgently needed. This study aimed to evaluate the efficacy and safety of chiglitazar, a PPAR pan-agonist, in MASLD with hypertriglyceridemia and insulin resistance. APPROACH AND RESULTS:In this phase II multicenter, randomized, double-blind and placebo-controlled study, 104 patients with MASLD with hypertriglyceridemia and insulin resistance were randomized 2:2:1 to receive 48 mg, 64 mg of chiglitazar, or placebo once daily for 18 weeks. The primary endpoint was the percentage change in liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) at week 18. Chiglitazar significantly reduced liver fat content, with percentage change from baseline at week 18 of -28.1% (95% CI -37.5 to -18.7) in the 48 mg group and -39.5% (95% CI -49.0 to -30.0) in the 64 mg group, compared with -3.2% (95% CI -16.8 to 10.4) in placebo group. The differences compared with placebo were -24.9% ( p <0.05) for the 48 mg group and -36.3% ( p <0.001) for the 64 mg group. Chiglitazar also significantly improved liver injury-related biomarkers such as ALT, AST, and γ-GT. Liver fibrosis indicators, lipid parameters, insulin resistance, and metabolic syndrome showed an improved trend. Both doses of chiglitazar were well tolerated, with most adverse events being mild to moderate. CONCLUSIONS:Chiglitazar significantly reduced liver fat content in MASLD with hypertriglyceridemia and insulin resistance, with a dose-dependent effect and a favorable safety profile.