Drug-induced liver injury (DILI) is an important drug-induced disease in clinical practice, with a complex pathogenesis and challenges in diagnosis and treatment. Glycyrrhizin preparations are a class of hepatoprotective agents derived from the traditional Chinese medicinal plant Glycyrrhiza uralensis, and have shown significant efficacy in the treatment of DILI due to their multi-target and multi-pathway pharmacological effects. Currently, they have been recommended as core therapeutic drugs for DILI in multiple domestic and international guidelines. This review delves into the advanced evidence-based medical evidence for the treatment of DILI with glycyrrhizin preparations and their recommended status in various guidelines. It also systematically expounds the precise treatment strategies of glycyrrhizin preparations based on DILI classification, severity, and special populations, and elaborately analyzes their cutting-edge mechanisms of action such as regulation of the gut-liver axis and epigenetic modifications. It discusses the challenges in clinical application, such as adverse reactions and predictive markers of efficacy, and their optimization solutions, and looks forward to future research directions. This article aims to promote the precise application of glycyrrhizin preparations in the treatment of DILI, providing practical diagnostic and therapeutic references for clinicians.

Background and Aims:Recurrence remains common after minimally invasive treatment in patients with early-stage hepatocellular carcinoma (HCC). This randomized controlled trial evaluated the efficacy and safety of Yangyin Fuzheng Jiedu Prescription (YFJP) as an adjunct to minimally invasive treatment in early-stage HCC. Method:In this randomized controlled trial, 300 patients with early-stage HCC (BCLC stage 0-A) undergoing minimally invasive treatment were randomly assigned (1:1) to receive YFJP plus minimally invasive treatment (YFJP group) or minimally invasive treatment alone (Control group). Patients were followed for 48 weeks. The primary endpoint was recurrence-free survival (RFS). RFS was assessed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were used for exploratory subgroup analyses. Safety was evaluated by the incidence of adverse events. Result:At 48 weeks, outcome data were available for 135 patients in the YFJP group and 137 patients in the Control group. Recurrence-free survival was significantly longer in the YFJP group than in the Control group (log-rank p = 0.016). Subgroup analyses showed a generally consistent direction of treatment effect across clinical subgroups, although the magnitude of effect varied. The incidence of adverse events was similar between groups, with no unexpected safety signals observed. Conclusion:In patients with early-stage HCC undergoing minimally invasive treatment, adjunctive treatment with YFJP was associated with improved recurrence-free survival over 48 weeks without compromising safety. These findings support the potential role of YFJP as an adjunctive therapeutic option in early-stage HCC. Clinical Trial Registration:https://clinicaltrials.gov/, Identifier NCT04264962.

Natural killer (NK) cell immunosuppression represents a critical factor in patients with progressive hepatocellular carcinoma (HCC), yet its underlying characteristics at the single-cell level remain poorly defined. This study investigates the functional and metabolic alterations in NK cells associated with progressive HCC. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from six treatment-naïve HCC patients, categorised into progressive and stable disease groups based on a 3-year follow-up. This was complemented by multicolor flow cytometry of peripheral blood, alongside multicolor fluorescence analyses of paired tumour and adjacent tissues. Our analyses revealed a significant reduction in NK cell proportion and a marked downregulation of immune-related genes in patients with progressive HCC. scRNA-seq further identified a distinct NK cell characterised by high expression of HAVCR2 (TIM3). Compared to TIM3-NK cells, TIM3+NK cells exhibited an exhausted phenotype, evidenced by upregulated CD39 and TIGIT, impaired functional capacity (reduced CD107a and IFN-γ) and downregulated key glycolytic enzymes (HK2, ATP5a). Clinically, high TIM3 expression correlated with shorter progression-free survival and an increased risk of tumour progression. Collectively, our findings delineate a state of NK cell immunosuppression and metabolic impairment in progressive HCC, potentially driven by glycolytic reprogramming and establish TIM3 as a critical marker and potential therapeutic target.

BACKGROUND AND AIMS:Metabolic associated steatohepatitis (MASH) is a critical stage of MAFLD, lacking effective therapies. Gut microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), are increasingly recognised as modulators of hepatic metabolism and immune responses. We investigated whether Prevotella could ameliorate MASH by regulating CD8+ T-cell metabolism. METHODS:Faecal samples from MASH patients and healthy controls were analysed by 16S rDNA sequencing and untargeted metabolomics. MASH mouse models, germ-free mice and ex vivo CD8+ T-cell cultures were used to assess the effects of Prevotella and butyrate on glycolysis, PI3K/AKT/mTOR signalling and liver pathology. Metabolic activity was measured using ECAR, 2-NBDG uptake and lactate production; molecular changes were evaluated by qPCR, western blotting and flow cytometry. RESULTS:16S rDNA sequencing revealed a significant reduction of Prevotella abundance in MASH patients compared with healthy controls, which was inversely correlated with hepatic steatosis and CD8+ T-cell infiltration. In MCD diet-induced MASH mice, oral administration of Prevotella alleviated hepatic lipid accumulation and collagen deposition. In germ-free mice, colonisation with Prevotella similarly improved liver histology. Mechanistically, Prevotella suppressed glycolytic activity in CD8+ T cells, as shown by decreased 2-NBDG uptake, ECAR measurements and reduced expression of glycolytic enzymes (HK2, PKM2, LDHA). Additionally, Prevotella downregulated the PI3K/AKT/mTOR signalling pathway in CD8+ T cells, linking its metabolic effects to immune modulation. Notably, the combination of Prevotella with a glycolysis inhibitor did not further enhance its therapeutic efficacy compared with Prevotella alone, indicating that suppression of glycolysis is a major mechanism underlying Prevotella's protective effects. CONCLUSION:Prevotella mitigates MASH by downregulating the PI3K/AKT/mTOR-glycolysis axis in CD8+ T cells via butyrate-dependent mechanisms, highlighting its potential as a microbial therapeutic candidate for MASH.

Patients with Hepatitis B Virus-related liver failure are highly vulnerable to secondary infections (SI), yet early predictive tools remain limited. In this work, we aim to develop and validate a plasma proteomics-based model for early SI risk assessment. In a prospective multicenter study, 114 patients are enrolled in the discovery cohort, 60 each in two validation cohorts. Untargeted proteomics is used to identify SI-related proteins, followed by Minimum Redundancy Maximum Relevance based feature selection and logistic regression modeling. Targeted proteomics and ELISA are applied for external validation. Inflammatory and coagulation pathway dysregulation is strongly associated with SI. A final model including Lysozyme (LYZ), Calmodulin 1 (CALM1), Serpin Family D Member 1 (SERPIND1), Dermatopontin (DPT), total bilirubin, and AST show excellent discrimination (area under the receiver operating characteristic curve (AUROC) 0.980 in discovery; 0.873 in validation), outperforming C-reactive protein (CRP), white blood cell (WBC), and Neutrophil percentage (NE%). It also predicts 28-day mortality better than Chronic Liver Failure-Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF) and Model for End-Stage Liver Disease (MELD). ELISA measurements in validation cohort 2 yield consistent trends, and an ELISA-based model achieve an AUROC of 0.883. This proteomics-derived model reliably identifies patients at high SI risk and supports early clinical intervention.

Background:Despite the global prevalence of SARS-CoV-2 reinfection, relatively little is known regarding its association with osteoporosis in older adults. This study investigated the potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on bone health or osteoporosis risk in adults aged 55 years and older in Beijing, China, while also exploring additional factors that may influence this association. Methods:This cross-sectional study was conducted at Beijing Ditan Hospital, Beijing, China, between August and December 2024. Patients aged ≥ 55 years with SARS-CoV-2 infections were included. Data on demographic characteristics, lifestyle habits, diet, serum contents of 25-hydroxyvitamin D (25-OH-VD), and other potential risk factors for osteoporosis were collected through structured questionnaires. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry (DXA). To identify the variables associated with osteoporosis, logistic regression analysis was employed. Results:Three hundred and eighty-eight patients were enrolled, comprising 272 individuals with a single SARS-CoV-2 infection and 116 with two or more infections. The results revealed that individuals who had reinfection revealed a considerably higher prevalence of osteoporosis (48.3% vs. 17.3%, p < 0.0001). This trend was consistent across different skeletal sites: 33.6% vs. 7.4% at the left hip, 37.9% vs. 5.5% at the right hip (p < 0.0001), and 30.2% vs. 12.9% at the lumbar spine (L1-L4) (p < 0.0001). SARS-CoV-2 reinfection remained substantially associated with osteoporosis after controlling for con-founding variables, with an OR of 3.08 (95% CI: 1.696-5.593). Conclusion:In summary, the risk of osteoporosis among individuals with SARS-CoV-2 reinfection should be carefully monitored, and greater emphasis should be placed on early, individualized prevention and treatment strategies.

This study aims to develop a nomogram model intended for predicting long-term mortality in patients suffering from hepatitis B-related cirrhosis associated with Portal vein thrombosis (PVT). A total of 961 patients were recruited from January 2015 to December 2023, forming the training cohort. We analysed independent risk factors affecting 5-year mortality through COX regression, from which we constructed a nomogram. To assess the nomogram's utility, we employed the receiver operating characteristic (ROC) curve, C-index, calibration curves, and decision curve analysis (DCA). The independent prognostic factors retained in the final model for patients with hepatitis B-related cirrhosis complicated by PVT included age (HR = 1.09, 95% CI: 1.06-1.11; p < 0.001), leukocyte count (WBC) (HR = 1.09, 95% CI: 1.03-1.17; p = 0.002), and the neutrophil-to-lymphocyte ratio (NLR) (HR = 1.29, 95% CI: 1.22-1.35; p < 0.001), along with serum sodium (HR = 0.94, 95% CI: 0.90-0.98; p = 0.005). The AUROC values for the nomogram were 0.906 (95% CI: 0.891-0.921) in the training cohort and 0.910 (95% CI: 0.885-0.927) in the validation cohort, demonstrating improved performance and discriminatory ability compared to current models, including CTP and MELD scores. Age, leukocyte count (WBC), NLR, and serum sodium emerged as independent risk factors impacting prognosis for patients with hepatitis B cirrhosis and PVT within 5 years. The nomogram developed in this research holds significant potential for accurately predicting the outcomes of these patients within 5 years.

BACKGROUND:The portal vein thrombosis (PVT) can exacerbate portal hypertension and lead to complications, increasing the risk of mortality. AIM:To evaluate the predictive capacity of artificial neural networks (ANNs) in quantifying the likelihood of developing PVT in individuals afflicted with hepatitis B-induced cirrhosis. METHODS:A retrospective study was conducted at Beijing Ditan Hospital, affiliated with Capital Medical University, including 986 hospitalized patients. Patients admitted between January 2011 and December 2014 were assigned to the training set (685 cases), while those hospitalized from January 2015 to December 2016 were divided into the validation cohort (301 cases). Independent risk factors for PVT were identified using COX univariate analysis and used to construct an ANN model. Model performance was evaluated through metrics such as the area under the receiver operating characteristic curve (AUC) and concordance index. RESULTS:In the training set, PVT occurred in 19.0% of patients within three years and 23.7% within five years. In the validation cohort, PVT developed in 16.7% of patients within three years and 24.0% within five years. The ANN model incorporated nine independent risk factors: Age, ascites, hepatic encephalopathy, gastrointestinal varices with bleeding, Child-Pugh classification, alanine aminotransferase levels, albumin levels, neutrophil-to-lymphocyte ratio, and platelet. The model achieved an AUC of 0.967 (95%CI: 0.960-0.974) at three years and 0.975 (95%CI: 0.955-0.992) at five years, significantly outperforming existing models such as model for end-stage liver disease and Child-Pugh-Turcotte (all P < 0.001). CONCLUSION:The ANN model demonstrated effective stratification of patients into high- and low-risk groups for PVT development over three and five years. Validation in an independent cohort confirmed the model's predictive accuracy.

Transarterial chemoembolization (TACE) has the potential to activate the immune system and regulate the tumor microenvironment. This study assesses the clinical response of patients with HBV-related hepatocellular carcinoma (HBV-HCC) after TACE treatment based on systemic immune classification (SIC). A total of 80 patients with HBV-HCC were assessed for the peripheral blood immune exhaustion phenotype and immune proteins through a combination of “Olink High Sensitivity Plasma Proteomics” and “Multicolor Flow Cytometry.” An unsupervised clustering algorithm was employed to classify various immune subtypes and identify core indicators that evaluate the response of SIC to TACE treatment. The application of these two technologies as novel approaches for detecting HBV-HCC provides synergistic insights into disease mechanisms and patient prognosis. Based on the combination of immune exhaustion phenotypes and immune proteins, we developed SIC that classified the subjects into three clusters: Cluster 1, Cluster 2, and Cluster 3. Cluster 3 was associated with poor clinical characteristics, unfavorable prognosis, and elevated levels of immune checkpoint expression. This risk scoring system is capable of predicting the overall survival of patients at various time points, with receiver operating characteristic areas exceeding 0.8. This study establishes SIC method to predict the clinical response of HBV-HCC patients after TACE treatment, providing new guidance for future immunotherapy and identification of non-invasive biomarkers.

ABSTRACT Objective Malignant mesothelioma (MM) is a rare malignant tumor. To explore the clinicopathological characteristics and efficacy of Chinese population with MM in the real‐world. Methods Two hundred and forty‐eight patients diagnosed with MM between September 2007 and August 2024 from three large medical centers (Beijing Hospital, Peking University Cancer Hospital, and Chinese Academy of Medical Sciences Cancer Hospital) were retrospectively analyzed. Kaplan–Meier and Cox regression were performed. Breast cancer gene 1‐associated protein 1 ( BAP1 ) status was evaluated. Results Chinese population with MM had a lower diagnostic age, higher proportion of youth and female, more advanced stage and lower expression of characteristic markers. The median progression‐free survival (mPFS) and median overall survival (mOS) were 8.90 and 25.60 months for the first‐line treatment, and 3.28 and 19.50 months for the second‐line. The first‐line immunotherapy provided a relatively higher objective response rate (33.3% vs. 20.5%, p = 0.402) and a trend to prolong mPFS (12.10 vs. 9.20 months, p = 0.345) and mOS (NA vs. 23.90, p = 0.185) compared with chemotherapy. Bevacizumab combined with chemotherapy relatively prolonged mPFS (10.47 vs. 7.93 months, p = 0.074) and mOS (31.30 vs. 23.20 months, p = 0.673) than chemotherapy alone. Carboplatin relatively improved mPFS than cisplatin (10.87 vs. 8.87 months, p = 0.185). Age and histologic type were predictors for PFS, and gender, histologic subtype, and CK5/6 were prognosis factors for OS. Briefly, 17.78% patients existed BAP1 deletions and correlated with OS benefit. Conclusion Chinese population with MM present unique clinicopathologic characteristics and could benefit from the first‐line immunotherapy and bevacizumab combined with chemotherapy. Gender, histologic subtype, and CK5/6 are prognosis factors for OS. BAP1 deletions correlate with OS benefit.

BACKGROUND:Pien Tze Huang (PTH), a well-established traditional Chinese medicine compound, has exhibited anti-hepatic fibrosis properties both in vitro and in vivo animal models, but the randomized clinical trials to evaluate anti-hepatic fibrosis efficacy of PTH are deficient. Chronic hepatitis B (CHB) is a leading cause of hepatic fibrosis in China. Although antiviral therapies have demonstrated significant effectiveness in arresting the progression of fibrotic disease, complete regression of established fibrosis is limited to only a subset of treated patients. PURPOSE:To assess the efficacy of PTH in improving hepatic fibrosis in CHB patients. STUDY DESIGN:We conducted a randomized, double-blind, placebo-controlled clinical trial involving 144 CHB patients with hepatic fibrosis. This study was carried out from September 2020 to April 2023. (Clinical Trials Registration: ChiCTR2000035128) METHODS: CHB patients with an Ishak score of 2-5 points were recruited from ten hospitals across China. Participants were randomized in 1:1 ratio to receive either oral PTH (0.6 g per dose, three times/day) or placebo for 48 weeks, in addition to the standard treatment of entecavir (0.5 mg/day). The primary endpoint was the change in Ishak score. Secondary outcomes included changes in Knodell HAI score, liver stiffness measurement, AST- to -platelet ratio index, Fibrosis-4 index and hepatic function indices. RESULTS:Of the 144 randomized patients, 142 patients (71 in the PTH group and 71 in the placebo group) were included in the primary analysis. The PTH group exhibited lower Ishak score compared to the control group (2.37 ± 0.94 vs. 2.87 ± 1.04, F = 6.072, p = 0.015). Notably, in treatment-naive patients, the PTH group showed significant improvement in Ishak score post-treatment compared with the control group (2.13 ± 0.72 vs. 2.74 ± 1.07, F = 6.336, p = 0.014). However, no significant changes were observed in these parameters among patients already receiving antiviral therapy. CONCLUSIONS:The combination of PTH and entecavir demonstrates significant improvement in hepatic fibrosis among CHB patients, especially those who are treatment-naive patients.

BACKGROUND There is insufficient evidence on the evaluation of liver fibrosis in Asian individuals with primary biliary cholangitis (PBC) using vibration-controlled transient elastography (VCTE). AIM To assess advanced fibrosis (AF) using liver stiffness measurement (LSM) in Chinese patients with PBC. METHODS In total, 277 Chinese patients diagnosed with PBC who underwent liver biopsy and VCTE were retrospectively included and categorized into the derivation and validation cohorts. The areas under the receiver operating characteristic curves (AUROCs) with 95% confidence intervals (CIs) were used to estimate the diagnostic accuracy of LSM for AF (Ludwig stage ≥ III). Multivariable analysis was performed using logistic regression. RESULTS In the derivation cohort, VCTE accurately detected patients with AF, achieving an AUROC of 0.93 (95%CI: 0.88-0.96). AF was independently predicted by LSM according to multivariable analysis. AF can be excluded and confirmed using LSM cutoffs of ≤ 10.0 and > 14.5 kPa, respectively, with a sensitivity of 0.91, negative predictive value of 0.93, specificity of 0.96, positive predictive value of 0.92, and an error rate of 7.5%. The accuracy of these values was validated in an independent cohort, achieving an AUROC of 0.97 (95%CI: 0.90-0.99) for AF with a sensitivity of 0.89, negative predictive value of 0.88, specificity of 0.95, positive predictive value of 0.94, and error rate of 9.0%. Compared with serum fibrosis markers, the AUROC of LSM was significantly higher in both the derivation and validation cohorts. CONCLUSION VCTE has a high accuracy for assessing AF in Chinese patients with PBC in a real-world setting.

Traditional Chinese medicine (TCM) has become a standardized medical system through systematic development across global healthcare practices. However, concerns persist regarding the safety, efficacy and quality of traditional medicinal products. Traditional Chinese medicine regulatory science (TCMRS) has emerged as an interdisciplinary field to address these challenges. This discipline integrates multidisciplinary knowledge to develop new tools, standards and approaches for systematic evaluation of benefit-risk profiles. This approach aims to ensure the quality, safety, and efficacy of TCM products, while also supporting the development of scientifically grounded regulatory frameworks that accommodate traditional medicine's distinctive characteristics. Through comprehensive quality management from raw material sourcing to production processes and clinical validation, developing and adopting TCMRS is entrusted to significantly strengthen its regulatory oversight. This review examines the critical scientific challenges in the modernization process of TCM, analyzes the conceptual foundations of TCMRS, evaluates its pivotal role in pharmaceutical transformation, and highlights its essential function in preserving traditional knowledge while fostering therapeutic innovation. Key challenges for TCMRS implementation include reconciling traditional epistemologies with modern pharmaceutical paradigms, standardizing complex herbal formulations, and developing rigorous evaluation protocols for decoctions and compound preparations. The integration of advanced methodologies, including systems biology, network pharmacology, artificial intelligence, and nanotechnology, into regulatory frameworks, combined with enhanced international cooperation, remains a crucial strategy for tackling global public health challenges. Future development trajectories for TCMRS will prioritize lifecycle management strategies, technology-driven innovation systems, and global knowledge-sharing initiatives, propelled by advancements in life sciences and information technology. This evolution requires careful balancing of three fundamental elements: theoretical development in traditional medicine, integration of emerging technologies, and maintenance of regulatory system stability. It is crucial to innovate the working mechanisms of the TCMRS researcher alliance and the global policy-coordination mechanism for TCM regulation, enhance the conversion of basic disciplines into regulatory applications, and support the establishment of an excellent TCM regulatory system with scientific decision-making. These efforts are essential for promoting the high-quality development of the TCM industry and boosting its international influence and presence.

Alcoholic liver disease (ALD) serves as the leading cause of chronic liver diseases-related morbidity and mortality, which threatens the life of millions of patients in the world. However, the molecular mechanisms underlying ALD progression remain unclear. Here, we applied microarray analysis and experimental approaches to identify miRNAs and related regulatory signaling that associated with ALD. Microarray analysis identified that the expression of miR-99b was elevated in the ALD mouse model. The AML-12 cells were treated with EtOH and the expression of miR-99b was enhanced in the cells. The expression of miR-99b was positively correlated with ALT levels in the ALD mice. The microarray analysis identified the abnormally expressed mRNAs in ALD mice and the overlap analysis was performed with based on the differently expressed mRNAs and the transcriptional factors of miR-99b, in which STAT1 was identified. The elevated expression of STAT1 was validated in ALD mice. Meanwhile, the treatment of EtOH induced the expression of STAT1 in the AML-12 cells. The expression of STAT1 was positively correlated with ALT levels in the ALD mice. The positive correlation of STAT1 and miR-99b expression was identified in bioinformatics analysis and ALD mice. The expression of miR-99b and pri-miR-99b was promoted by the overexpression of STAT1 in AML-12 cells. ChIP analysis confirmed the enrichment of STAT1 on miR-99b promoter in AML-12 cells. Next, we found that the expression of mitogen-activated protein kinase kinase 1 (MAP2K1) was negatively associated with miR-99b. The expression of MAP2K1 was downregulated in ALD mice. Consistently, the expression of MAP2K1 was reduced by the treatment of EtOH in AML-12 cells. The expression of MAP2K1 was negative correlated with ALT levels in the ALD mice. We identified the binding site of MAP2K1 and miR-99b. Meanwhile, the treatment of miR-99b mimic repressed the luciferase activity of MAP2K1 in AML-12 cells. The expression of MAP2K1 was suppressed by miR-99b in the cells. We observed that the expression of MAP2K1 was inhibited by the overexpression of STAT1 in AML-12 cells. Meanwhile, the apoptosis of AML-12 cells was induced by the treatment of EtOH, while miR-99b mimic promoted but the overexpression of MAP2K1 attenuated the effect of EtOH in the cells. In conclusion, we identified the correlation and effect of STAT1, miR-99b, and MAP2K1 in ALD mouse model and hepatocyte. STAT1, miR-99b, and MAP2K1 may serve as potential therapeutic target of ALD.

Background and aim: The prevalence and adverse outcomes of metabolic dysfunction associated with steatotic liver disease (MAFLD) are increasing. The changes in the gut microbiota and metabolites associated with metabolic dysfunction-associated steatohepatitis (MASH) are regarded as an essential part of the progression of MAFLD. This study aimed to identify the gut microbiota and metabolites involved in the development of MAFLD in patients. Method: This study enrolled 90 patients (healthy controls, HC: n = 30; MASH: n = 30; MASH-related cirrhosis, MC: n = 30), and their fecal samples were collected for 16S rRNA sequencing and non-targeted LC–MS/MS metabolomics analysis. Data preprocessing and statistical analyses were performed using QIIME2 software, Pynast, QIIME2 package, Progenesis QI, and R program. Results: The abundance of Prevotellaceae at the family level and Prevotella at the genus level was lower in the MASH and NC samples than in the HC samples. Both Prevotellaceae and Prevotella showed the strongest correlation with MASH progression via random forest analysis. Untargeted metabolomics was used to quantitatively screen for discrepant metabolites in the stool samples from the three groups. Linolenic acid (LA)-related metabolite levels were significantly lower in MASH and NC samples. Associations between Prevotella- or LA-related metabolites and liver function were discovered. A high abundance of Prevotella was associated with LA-related metabolites and MASH. Conclusion: This study identified that gut microbiota and metabolites are associated with MASH-related metabolic dysfunction. LA and Prevotella are depleted during MASH progression, and additional supplementation with Prevotella may be a potential strategy for the future treatment of MAFLD.