BACKGROUND Real-world data remain limited on the effectiveness of magnesium isoglycyrrhizinate (MgIG) for post hepatectomy liver injury. We hypothesize that perioperative MgIG is effective as a management strategy against hepatic injury in patients undergoing hepatectomy. AIM To evaluate the prophylactic and therapeutic effectiveness of MgIG for hepatic injury in patients undergoing hepatectomy in a real-world setting. METHODS We retrospectively reviewed the clinical data of consecutive Chinese patients who underwent hepatectomy between March 2020 and March 2023 at two tertiary care hospitals in China. The cohorts were balanced using propensity score matching (PSM). The primary outcome was the prevalence of postoperative liver injury, defined as >= 3 & times; upper limit of normal of the serum levels of alanine aminotransferase (ALT) or aspartate aminotransferase. RESULTS The rate of postoperative liver injury was 76.9% among 1711 eligible patients. After PSM, patients who received perioperative MgIG had a significantly greater reduction in the prevalence of liver injuries than those who only received postoperative MgIG on postoperative day (POD) 3 (53.3% vs 69.1%; P = 0.006) and POD 7 (14.2% vs 23.6%; P = 0.027). The proportions of patients with >= 50% reduction in ALT were significantly higher in patients treated with MgIG plus other liver protectants than those treated with other liver protectants on POD 3 and 7, and upon hospital discharge. Multivariable analysis indicated an independent protective role of prophylactic MgIG in postoperative liver injury. CONCLUSION This study indicates that the addition of preoperative prophylaxis to postoperative treatment with MgIG can mitigate of the rise of aminotransferases and enhance postoperative liver function recovery, conferring benefits on more surgical patients.

Background:Pyroptosis is a significant contributor to the development of severe acute pancreatitis (SAP), and the presence of SAP together with a reduced platelet count often indicates a poor prognosis. In this study, we screened targets from platelets and explored the role of lectin galactoside-binding soluble 9 (LGALS9) in acinar cell pyroptosis and inflammation in SAP. Methods:SAP cell models, alongside mouse models showing diminished platelet counts, were established using caerulein and lipopolysaccharide. We conducted transcriptomic sequencing on platelets from mice with and without SAP to identify possible targets, and we determined LGALS9 levels in platelet releasates and serum from both patients and mice with and without SAP. Bioinformatic analysis was then applied to predict the relationship between LGALS9 and pyroptosis-related proteins. Subsequently, recombinant LGALS9, α-lactose, and RG9-35 were used to treat SAP mice and acinar cells to evaluate the effect of LGALS9 on inflammation and its regulatory effects on acinar cell pyroptosis in SAP. Results:LGALS9 expression was upregulated in SAP platelets, and LGALS9 levels were found to be significantly elevated in platelet releasates and serum. Bioinformatic analysis illustrated the correlations and interactions between LGALS9 and the pyroptosis-related proteins ASC, NLRP3, caspase-1, and gasdermin D. Within the SAP context, LGALS9 may be potentially administered to diminish acinar cell pyroptosis-related protein levels, inhibit acinar cell pyroptosis, mitigate inflammatory factor levels, and alleviate pancreatic tissue inflammatory damage. Conclusion:Our data indicated that LGALS9 expression was elevated in platelets of patients and mice with SAP. LGALS9 also inhibited NLRP3 inflammasome-dependent pyroptosis and suppressed inflammation in SAP.

Metastatic colorectal cancers (mCRCs) exhibit substantial heterogeneity at the genetic, transcriptomic, histological, and microenvironmental levels, which contributes to therapeutic resistance and variable clinical outcomes. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) have emerged as powerful platforms for modeling this complex disease. PDOs faithfully recapitulate tumor architecture, molecular features, and heterogeneity, enabling high-throughput drug screening and personalized treatment response prediction. In addition, PDX models maintain tumor–stroma interactions in vivo and accurately reflect histological and pharmacological phenotypes, supporting studies on treatment response and resistance mechanisms. Recent advances indicate that these models capture intratumoral, intertumoral, and interpatient variability; reveal patterns and mechanisms of drug sensitivity heterogeneity; and can be used to predict chemotherapy efficacy. However, limitations remain for both model types. Innovations such as humanized PDX mouse models and immune‒organoid coculture systems are being developed to overcome these barriers. This review summarizes the latest progress in PDO and PDX applications in research on mCRC heterogeneity, highlights their role in dissecting tumor heterogeneity, and discusses future directions for integrating these models into precision oncology.

Background Perioperative use of immune checkpoint inhibitors (ICIs) in patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT) remains controversial, primarily because of concerns regarding allograft rejection. The present study evaluated the safety and potential efficacy of ICIs as a downstaging or bridging therapy prior to LT. Methods This multicenter retrospective analysis included 17 patients with HCC from six Chinese centers who received at least one cycle of preoperative ICI therapy followed by LT. Results The cohort had a mean age of 51.1 u00B1 9.9 years; 94.1% were men. Disease stages were Barcelona Clinic Liver Cancer Stage A (n = 2), B (n = 10), and C (n = 5). All patients received multimodal therapy combining ICIs (sintilimab, n = 13; tislelizumab, n = 2; atezolizumab, n = 1; and pembrolizumab, n = 1) with locoregional and/or systemic treatments. In accordance with the Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 76.5% (13/17), comprising 1 complete response and 12 partial responses. Following LT, all patients received a tacrolimusu2010based immunosuppressive regimen. Over a median followu2010up of 11.4 months, no indications of graft rejection and no tumor recurrence were observed. Conclusion In the study cohort, preoperative ICIu2010based therapy was not associated with an increased risk of rejection, suggesting its shortu2010term safety in the context of LT for HCC. Larger prospective studies are warranted to validate these findings and to further define the efficacy and safety profile of this approach.

Radiotherapy stands as a cornerstone in cancer therapy, with nuclear DNA acknowledged as the principal target molecule for radiation-induced cellular demise or injury. Nonetheless, an expanding body of contemporary research elucidates the significant contri-bution of sphingolipids to radiation-induced cell death, particularly in modulating radiation-induced apoptosis. Radiation can instigate apoptosis through multiple pathways of sphin-golipid metabolism, encompassing the activation of ceramide synthase, acid sphingomyelin-ase, neutral sphingomyelinase, sphingosine-1-phosphate lyase, and sphingosine-1-phosphate phosphatase, and the inhibition of sphingosine kinase-1. The disruption of sphingolipid me-tabolism leads to an increase in pro-apoptotic sphingolipid ceramide and sphingosine and a decrease in anti-apoptotic sphingolipid sphingosine-1-phosphate, which ultimately triggers apoptosis in tumor cells. The diminished or absent response of sphingolipids to radiation rep-resents one of the contributors to radioresistance. In this context, numerous interventions tar-geting sphingolipids have been utilized to augment radiosensitivity in tumor tissue and miti-gate radiation-induced damage in normal tissue, demonstrating efficacy both in vitro and in vivo. Sphingolipids have also emerged as promising biomarkers for evaluating the response to radiotherapy in patients. Attaining a comprehensive understanding of sphingolipid metab-olism in radiation-induced apoptosis holds the potential to offer an effective strategy for en-hancing the efficacy of radiotherapy and mitigating resistance to such treatment.

BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), significantly contribute to the increasing incidence of liver cancer due to NASH (NALC), emphasizing the urgent need to address the associated global health burden. METHODS:Using the Global Burden of Disease 2021 dataset, we analyzed the incidence, mortality, and disability-adjusted life year (DALY) rates of NALC and NAFLD from 1990 to 2021 across 204 countries. The Joinpoint model, age-period-cohort modeling, decomposition analysis, and frontier analysis were used to assess trends, identify contributing factors, and evaluate health inequities. Projections for future incidence were made using Nordpred and Bayesian age-period-cohort models. RESULTS:The global incidence and mortality rates of NALC have increased significantly. Incidence rose from 14,413.92 cases (95% CI 11,470.95-17,854.24) in 1990 to 42,291.37 (95% CI 34,032.64-51,129.45) in 2021. This trend was particularly evident in low-middle SDI countries, while high SDI countries exhibited declining mortality rates despite rising incidence. Population growth was a primary driver of the increased burden in most regions. Projections suggest that NALC incidence may reach 43,525.53 (95% CI 14,169.28-72,881.77) by 2039, particularly among the elderly, highlighting the serious future risks associated with NALC globally. CONCLUSION:The findings highlight the growing global burden of NALC driven by NAFLD, especially in low- to middle-income regions. Targeted interventions, alongside a deeper understanding and better resource allocation, are essential to mitigate the rising incidence and address the health disparities associated with this expanding public health challenge.

Background Post-hepatectomy liver failure (PHLF), defined as acute liver failure following hepatectomy, remains a major complication for postoperative mortality lacking early detection approaches. This study aimed to leverage cutting-edge artificial intelligence (AI) techniques for extensive temporal feature analysis using perioperative data, to advance the detection of PHLF to the first 24 h after surgery. Methods This nationwide multicenter retrospective study was conducted with a total of 1832 patients across six geographically diverse hospitals in China. This China cohort was divided into 681 cases for training the deep-learning model and 1151 cases for validation. Perioperative electronic health record (EHR) data were collected for each patient, including the basic characteristics and preoperative, intraoperative, and early postoperative factors within the first 24 h after surgery. 242 cases from the Medical Information Mart for Intensive Care (MIMIC)-IV database, predominantly comprising Caucasian patients with limited perioperative EHR data, were included to assess robustness in Western populations. PHLF was diagnosed by concurrent elevated prothrombin time/INR and hyperbilirubinemia on or after postoperative day 5 and graded according to the International Study Group of Liver Surgery criteria. The proposed algorithm employed a powerful foundation model (Bio-Clinical Bidirectional Encoder Representation from Transformers) and a context-aware transformer module to perform in-depth temporal feature investigation of perioperative data to enable early detection of PHLF. Our approach was compared with state-of-the-art machine learning and deep learning methods. T-distributed stochastic neighbor embedding and Shapley additive explanation analysis were conducted for model interpretability. The versatility of our model for routine clinical practice was systematically evaluated. This study is registered with ClinicalTrials.gov (NCT06532214). Findings Our model demonstrated high accuracy in detecting PHLF within the first 24 h after surgery, achieving an AUC of 0.952 in internal validation and 0.884 in external validation of the China cohort, outperforming other competing algorithms. In the MIMIC-IV cohort with challenging incomplete EHR data, our model had an AUC of 0.654, which was still superior to alternative algorithms, indicating generalization potential for the Western population. Interpretability analysis showed that our model could effectively encode all perioperative factors into discriminative high-dimensional feature embeddings with temporal correlations into consideration. Importantly, our model holds clinically acceptable interpretability that the patients with model-detected PHLF are likely experiencing the onset of liver failure comprehensively driven by reduced liver volume, extensive surgical injury, and underlying liver disease. Further evaluation demonstrated that our model is of superior versatility to support perioperative phase-agnostic PHLF prediction, risk stratification for PHLF, and incomplete variable inputs. Importantly, our model demonstrates a high capacity for predicting clinically relevant PHLF. The clinicians' prediction assisted by our model was substantially improved over the clinician-only predictions (AUC = 0.778 vs. 0.637, P = 0.009). Interpretation Our model achieved state-of-the-art performance in accuracy, generalizability, interpretability, and versatility for early detection of PHLF within the first 24 h after surgery. This approach holds promise for transforming perioperative management of hepatectomy and improving the rescue of life-threatening PHLF. Funding The work was partially supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project Reference Number: T45-401/22-N), in part by grants from the National Natural Science Foundation of China (82170647, 82270661, and 62372441), in part by grants from the Basic and Applied Basic Research Foundation of Guangdong Province (2023A1515010088, 2024A1515013204, and 2023A1515030268) and in part by grant from Shenzhen Science and Technology Program (Grant No. RCYX20231211090127030).

Accurate stratification of recurrence risk after curative resection remains a critical challenge in the management of hepatocellular carcinoma (HCC). Dysregulated ceramide (CER) metabolism has been implicated in HCC progression and relapse. This paper evaluates whether preoperative plasma CER profiling coupled with machine learning (ML) enhances the risk prediction of HCC recurrence. In this retrospective study, 257 HCC patients undergoing curative resection participated. Preoperative plasma CERs were quantified by targeted Lipidomics. Independent predictors were identified via multivariate Cox regression and incorporated into ten ML models. Using an internal 20

This study investigates the effects of fat emulsion-based early parenteral nutrition in patients following hemihepatectomy, addressing a critical gap in clinical knowledge regarding parenteral nutrition after hemihepatectomy. We retrospectively analysed clinical data from 274 patients who received non-fat emulsion-based parenteral nutrition (non-fatty nutrition group) and 297 patients who received fat emulsion-based parenteral nutrition (fatty nutrition group) after hemihepatectomy. Fat emulsion-based early parenteral nutrition significantly reduced levels of post-operative aspartate aminotransferase, total bilirubin and direct bilirubin, while minor decreases in red blood cell and platelet counts were observed in the fatty nutrition group. Importantly, fat emulsion-based early parenteral nutrition shortened lengths of post-operative hospital stay and fasting duration, but did not affect the incidence of short-term post-operative complications. Subgroup analyses revealed that the supplement of n-3 fish oil emulsions was significantly associated with a reduced inflammatory response and risk of post-operative infections. These findings indicate that fat emulsion-based early parenteral nutrition enhances short-term post-operative recovery in patients undergoing hemihepatectomy.

Abstract Background & aims We aimed to describe the dose–response relationship between daily step counts and intensity with respect to all–cause mortality among US adults diagnosed with metabolic dysfunction–associated steatotic liver disease (MASLD). Methods Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2005 to 2006, a cross–sectional study included 1,108 participants was performed to assess the relationship between daily step counts and step intensity with mortality. Results A total of 1,108 participants from the NHANES study were included, with a mean age of 49.5 ± 0.9 years. The sample consisted of 533 (48.1%) women, 809(73%) non–Hispanic whites, 122 (10.8%) non–Hispanic blacks, 133 (12.0%) Hispanic, and 44 (4.2%) individuals of other racial backgrounds. Using multivariable–adjusted Cox proportional hazards models, we found that compared to participants in the light–step group, there was significantly lower risk of mortality in the moderate (hazard ratio [HR], 0.47 [95% CI, 0.32–0.69]), high (HR, 0.35 [95% CI, 0.21–0.61]) and vigorous (HR,0.45 [95% CI, 0.22–0.93]) step groups. Sensitivity and subgroup analyses confirmed that the association between step count and mortality remained robust. However, after adjusting for all covariates, greater step intensity was not significantly associated with lower mortality. Further analysis revealed that age, BMI, and self–rated health could have confounded the relationship between step intensity and survival, potentially obscuring any direct effect of step intensity on mortality. Conclusions Accumulating a higher number of daily steps, rather than focusing on step intensity, was associated with a lower risk of all–cause mortality in individuals with MASLD. Our findings suggest that achieving 10,000 steps per day may be optimal for reducing the risk of all–cause mortality risk in this population.

The hepatic immune microenvironment governs liver disease susceptibility by balancing immune defense and tolerance. While phthalate esters (PAEs), emerging pollutants derived from plastics, have been acknowledged as hepatoxic substances, the immunomodulatory and clinical impacts of subacute PAEs exposure remain underexplored. In this study, we identified dibutyl phthalate (DBP) as a predominant PAE in liver tissues from hepatitis B virus (HBV)-infected patients. Based on the murine model mimicking specific scenarios of subacute DBP exposure, single-cell RNA sequencing and flow cytometry revealed that DBP significantly depleted hepatic T cells and induced functional exhaustion. Moreover, HBV-carrier mice exposed to DBP sub-acutely exhibited prolonged viral persistence, delayed HBsAg clearance and heightened liver injury markers. The co-culture assays mechanistically linked the persistent HBV infection to T cell dysfunction in the context of DBP exposure. Epidemiological analyses further correlated elevated urinary DBP metabolites with increased positivity of HBV indicators. Among individuals with HBV infection history, higher DBP metabolite levels were associated with reduced liver function. In conclusion, our findings elucidated that subacute DBP exposure exacerbates HBV progression by driving T cell exhaustion and synergistically leading to the collapse of hepatic immune microenvironment. Therefore, we propose DBP as a facilitator of HBV, positioning subacute DBP exposure as risk factors for viral hepatitis, advocating for monitoring of PAEs in high-risk populations and therapeutic strategies targeting immune exhaustion to mitigate PAEs-viral synergism in liver diseases.

Bile acid overload critically drives the pathogenesis of cholestatic liver injury (CLI). While ceramide metabolism has garnered increasing interest in liver research, the role of ceramides in CLI remains unclear. This study investigates the function of alkaline ceramidase 3 (ACER3)-catalyzed hydrolysis of unsaturated ceramides in CLI. Using clinical specimens, this work finds that ACER3 expression is upregulated in the cholestatic liver and positively correlated with the severity of CLI in patients. Acer3 ablation increases ceramide(d18:1/18:1) and attenuates bile duct ligation-induced CLI in female mice with reduced hepatic necrosis, inflammation, and fibrosis. However, it does not significantly impact CLI in male mice. Moreover, ceramide(d18:1/18:1) treatment attenuates CLI in wild-type female mice. Similarly, ACER3 knockdown and ceramide(d18:1/18:1) treatment prevent lithocholic-acid-induced cell death in human-liver-derived HepG2 cells. Mechanistically, ceramide(d18:1/18:1) binds the ligand binding domain of the liver X receptor β, acting as an agonist to activate its transcriptional functions. This activation upregulates sulfotransferase 2A1-catalyzed bile acid sulfation, normalizes bile acid metabolism, and restores lipogenesis, thereby reducing bile acid overload in hepatocytes to attenuate CLI. Our findings uncover the role of ceramide(d18:1/18:1)-liver X receptor β signaling in mitigating bile acid overload in the cholestatic liver, offering mechanistic insights and suggesting therapeutic potential for targeting ACER3 and ceramide(d18:1/18:1) for CLI.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, while the hepatocyte mechanisms driving oncogenesis remains poorly understood. In this study, single-nucleus RNA sequencing of samples from 22 HCC patients revealed 10 distinct hepatocyte subtypes, including beneficial Hep0, predominantly malignant Hep2, and immunosuppressive Hep9. These subtypes were strongly associated with patient prognosis, confirmed in TCGA-LIHC and Fudan HCC cohorts through hepatocyte composition deconvolution. A quantile-based scoring method is developed to integrate data from 29 public HCC datasets, creating a Quantile Distribution Model (QDM) with excellent diagnostic accuracy (Area Under the Curve, AUC = 0.968-0.982). QDM was employed to screen potential biomarkers, revealing that PDE7B functions as a key gene whose suppression promotes HCC progression. Guided by the genes specific to Hep0/2/9 subtypes, HCC is categorized into metabolic, inflammatory, and matrix classes, which are distinguishable in gene mutation frequencies, survival times, enriched pathways, and immune infiltration. Meanwhile, the sensitive drugs of the three HCC classes are identified, namely ouabain, teniposide, and TG-101348. This study presents the largest single-cell hepatocyte dataset to date, offering transformative insights into hepatocarcinogenesis and a comprehensive framework for advancing HCC diagnostics, prognostics, and personalized treatment strategies.

BACKGROUND:Circulating ceramides (CERs) are associated with liver diseases and dysfunction. The utility of plasma CERs in predicting post-hepatectomy liver failure (PHLF) remains unclear. This study aimed to evaluate the clinical utility of preoperative plasma CERs for predicting clinically relevant PHLF (CR-PHLF). METHODS:This study included 736 patients who underwent hepatectomy across four independent hospitals in China. The training set included 392 patients from 2019 to 2021, and the prospective internal and external validation sets included 195 patients from 2022 to 2024 and 149 patients from 2023 to 2025, respectively. Preoperative plasma CERs were measured using targeted lipidomics. Grade B/C PHLF was classified by the criteria of the International Study Group of Liver Surgery and defined as CR-PHLF. Predictors for CR-PHLF were identified by least absolute shrinkage and selection operator logistic regression and receiver operating characteristic analysis. The study is registered on ClinicalTrials.gov (NCT03598465) and the Research Registry (Identifier: researchregistry11253). RESULTS:Plasma CER(d18:1/20:1) demonstrated a positive correlation with preoperative liver dysfunction and superior predictive power for CR-PHLF, with an area under the receiver-operating characteristic curve (AUROC) of 0.837 (95% confidence interval [CI]: 0.782-0.892; P < 0.001). Major hepatectomy, direct bilirubin, and CER(d18:1/20:1) were identified as independent PHLF predictors and integrated into an innovative CR-PHLF prediction model (Hpx-CER model). The model exhibited commendable discrimination in the training set (AUROC = 0.896; 95% CI: 0.851-0.941; P < 0.001), and the prospective internal (AUROC = 0.907; 95% CI: 0.845-0.970; P < 0.001) and external validation sets (AUROC = 0.862; 95% CI: 0.707-1.000; P < 0.001). Across all high-risk subgroups of CR-PHLF, including major hepatectomy, difficult hepatectomy, cirrhosis, malignant liver diseases, and preoperative liver dysfunction, our model consistently outperformed conventional models in predicting CR-PHLF. CONCLUSION:Plasma CER(d18:1/20:1) is a novel predictor of CR-PHLF. The Hpx-CER model performs commendably in predicting CR-PHLF and provides reliable preoperative risk estimations.

Oxidative stress driven by malfunctioning respiratory complex I (RC-I) is a crucial pathogenic factor in liver ischemia/reperfusion (I/R) injury. This study investigated the role of alkaline ceramidase 3 (ACER3) and its unsaturated long-chain ceramide (CER) substrates in regulating liver I/R injury through RC-I. Our findings demonstrated that I/R upregulated ACER3 and decreased unsaturated long-chain CER levels in human and mouse livers. Both global and hepatocyte-specific Acer3 ablation, as well as treatment with CER(d18:1/18:1), led to a significant increase in CER(d18:1/18:1) levels in the liver, which mitigated the I/R-induced hepatocyte damage and inflammation in mice. Mechanistically, ACER3 modulated CER(d18:1/18:1) levels in mitochondria-associated membranes and the endoplasmic reticulum (ER), thereby influencing the transport of CER(d18:1/18:1) from the ER to mitochondria. Acer3 ablation and CER(d18:1/18:1) treatment elevated CER(d18:1/18:1) in mitochondria, where CER(d18:1/18:1) bound to the RC-I subunit NDUFA6 to inactivate RC-I and reduced reactive oxygen species production in the I/R-injured mouse liver. These findings underscore the role of the CER(d18:1/18:1)-NDUFA6 interaction in suppressing RC-I-mediated oxidative-stress-driven pathogenesis in liver I/R injury.

Background:Liver transplantation (LT) provides a potential cure for hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). We aimed to develop and externally validate a prognostic model to predict 1-year post-LT mortality in patients with HBV-ACLF. Methods:This retrospective, nationwide, observational cohort study was conducted at ten high-volume LT centres in China. 4378 adult patients who underwent primary LT between January 2015 and December 2021 were screened, and those with HBV-ACLF according to the COSSH-ACLF criteria (separated into three ACLF grades based on the number of organ failures) were included. The HBV-ACLF LT (HALT) model was developed in the derivation cohort and validated in the external testing cohort. The derivation cohort were derived from two LT centres in one province (Zhejiang). The external testing cohort were derived from eight LT centres in two provinces. For model development, univariable Cox regression analysis was used to identify risk factors associated with 1-year post-LT mortality. Variables with univariable p < 0.05 were entered into the least absolute shrinkage and selection operator (Lasso) analysis for further feature selection. 10-fold cross validation was used to choose the optimal lambda (penalty for the number of features) of the Lasso model. Multivariable Cox regression was applied to construct the HALT model based on the risk factors selected by Lasso analysis. Primary outcome was survival rate at 1-year after LT. Secondary outcomes were short-term (28- and 90-day) and long-term survival after LT (3- and 5-year). Model performance was compared with eight other models (COSSH-ACLF II, COSSH-ACLF, CLIF-C ACLF, AARC, MELD, MELD-Na, SALT-M and TAM scores), using receiver operating characteristic curve and C-index values. A nomogram was developed to analyse the probability of the primary outcome in different graft-recipient combinations based on recipient factors (age, number of organ failures [OF], lactate) and graft factors (donation after circulatory death [DCD] and cold ischaemia time [CIT]). Findings:Between Jan 1, 2015, and Dec 1, 2021, 668 patients were included (derivation cohort, n = 418; external testing cohort, n = 250), with survival rates of 88.0%, 81.1%, 77.5%, 75.6% and 72.1% at 28-day, 90-day, 1-year, 3-year and 5-year post-LT, respectively. Three recipient's factors (age, number of OF and arterial lactate concentration) as well as two graft's parameters (DCD and CIT) were independently associated with 1-year post-LT mortality in the derivation cohort (all p < 0.05). The HALT model was established accordingly, showing better discriminative performance (C-index, 0.791) than eight current models in the external testing cohort (C-index, 0.529-0.627; all p < 0.001). If the sickest patients (age >55 years, OFs ≥3 and lactate ≥2.5 mmol/L) received high-risk grafts (DCD and CIT >10 h), the estimated 1-year post-LT mortality was 85.6%. Interpretation:The HALT model showed superior predictive ability over eight current models and may help for LT candidate selection and optimal organ allocation. Though the findings need to be verified in prospective studies and among different patient populations. Funding:This work was supported by grants from the National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province, and the Research Project of Jinan Microecological Biomedicine Shandong Laboratory.

Liver fibrosis is a chronic liver disease with progressive wound healing reaction caused by liver injury. Currently, there is no FDA approved drugs for liver fibrosis. Human adipose mesenchymal stem cells (hADSCs) have shown remarkable therapeutic effects in liver diseases. However, few studies have evaluated the therapeutic role of hADSCs in liver fibrosis, and the detailed mechanism of action is unknown. Here, we investigated the in vitro and in vivo anti-fibrosis efficacy of hADSCs and identified important metabolic changes and detailed mechanisms through transcriptomic and metabolomic analyses. We found that hADSCs could inhibit the proliferation of activated hepatic stellate cells (HSCs), promote their apoptosis, and effectively inhibit the expression of pro-fibrotic protein. It can significantly reduce collagen deposition and liver injury, improve liver function and alleviate liver inflammation in cirrhotic mouse models. In addition, transcriptome analysis revealed that the key mechanism of hADSCs against liver fibrosis is the regulation of AGE-RAGE signaling pathway. Metabolic analysis showed that hADSCs influenced changes of metabolites in lipid metabolism. Therefore, our study shows that hADSCs could reduce the activation of hepatic stellate cells and inhibit the progression of liver fibrosis, which has important potential in the treatment of liver fibrosis as well as other refractory chronic liver diseases.

Background and Aims: Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs. Approach and Results: We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models. Conclusions: HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC.