Liver Research最新文献

{"title":"Targeting lactic acidosis in the tumor microenvironment: Enhancing TACE efficacy in hepatocellular carcinoma","authors":"Shuyi Hao ,&nbsp;Hong Yao ,&nbsp;Haojie Yu ,&nbsp;Lijun Wang ,&nbsp;Tingdong Yu ,&nbsp;Hongping Xia ,&nbsp;Yong Zha","doi":"10.1016/j.livres.2025.11.004","DOIUrl":"10.1016/j.livres.2025.11.004","url":null,"abstract":"<div><div>Lactic acidosis is a hallmark of the tumor microenvironment (TME) and a critical impediment to the efficacy of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Incomplete embolization preserves viable tumor cells that amplify hypoxia-driven glycolysis, generating a lactic acid-rich milieu that drives treatment resistance, skews immune populations toward immunosuppressive phenotypes, and impairs cytotoxic T lymphocyte function. In this review, we elucidate the pathways through which lactic acidosis compromises TACE efficacy and propose novel strategies for its mitigation. We examine emerging approaches, including systemic or intra-arterial alkalization, targeted inhibition of lactate production and export, and calcium carbonate nanoparticles, and evaluate their respective merits and limitations. Finally, we propose a combination regimen of calcium carbonate nanoparticles, lactate-targeting agents, and TACE to achieve precise drug delivery, synergistic lactic acid depletion, and enhanced antitumor immunity. These integrated strategies have the potential to convert immunologically “cold” HCC lesions into “hot” ones, thereby improving TACE outcomes and disease control.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 4","pages":"Pages 273-285"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer cachexia-related monocytic myeloid-derived suppressor cells impair T-cell negative selection and predict immune-related adverse events","authors":"Li Wei ,&nbsp;Ya-Qin Sun ,&nbsp;Jian-Hua Ren ,&nbsp;Ze-Xuan Huang ,&nbsp;Yuan Zhang ,&nbsp;Xiu-Qing Pang ,&nbsp;Xiao-Tong Lv ,&nbsp;Xiang-Yuan Wu ,&nbsp;Yan-Fang Xing ,&nbsp;Xing Li","doi":"10.1016/j.livres.2025.10.001","DOIUrl":"10.1016/j.livres.2025.10.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and aims&lt;/h3&gt;&lt;div&gt;Cancer cachexia is prevalent in various cancers and is associated with chemotherapy toxicity. However, limited data exist on the relationship between cachexia and immune-related adverse events (irAEs). The aim of this study is to explore the correlation between cancer cachexia and irAEs and its possible mechanism.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A murine model of orthotopic hepatocellular carcinoma (HCC) with cachexia was developed to evaluate the impact of T-cell infiltration into multiple tumor-free organs on the occurrence of irAEs. Single-cell RNA sequencing of thymic stromal cells was performed. Additionally, patients with advanced cancers receiving anti-programmed cell death protein 1/ligand 1 (PD-1/L1) antibody treatment were followed to investigate the relationship between cachexia and irAEs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Inflammatory cell infiltration was observed in multiple tumor-free organs of cachexic HCC mice but not in non-cachexic controls. Immunofluorescence confirmed that the infiltrating cells included CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cells. Morphological assessment and hematoxylin–eosin staining revealed thymic atrophy in cachexic HCC mice. Single-cell RNA sequencing of thymic stromal cells showed a reduction in medullary thymic epithelial cells (mTECs) II and III in cachexic mice. Autoimmune regulator (Aire) downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs. T cells from cachexic HCC mice induced organ-specific inflammation and T-cell infiltration in multiple organs of tumor-free mice. Following anti-mouse PD-1 antibody treatment, the incidence of inflammation in multiple organs markedly increased in cachexic HCC mice and in tumor-free mice that had received T cells from the cachexic HCC mice. Flow cytometry and immunofluorescence analyses revealed enrichment of thymic monocytic myeloid-derived suppressor cells (M-MDSCs) in cachexic HCC mice. M-MDSCs infiltrated the thymus in cachexic mice with cancer, and they induced apoptosis of mTECs from tumor-free mice &lt;em&gt;in vitro&lt;/em&gt; via nitric oxide production. Transfer of M-MDSCs led to inflammatory cell infiltration in multiple organs and thymic involution in tumor-free mice without affecting body weight. Sixty-four patients with advanced cancer receiving anti-PD-1/L1 therapy were enrolled. Patients who developed irAEs had higher levels of circulating M-MDSCs than those who did not. Moreover, patients with cachexia (body mass index (BMI) &lt; 20 kg/m&lt;sup&gt;2&lt;/sup&gt; or ≥5% weight loss over the past 6 months) had elevated M-MDSC levels. Patients with both high M-MDSC levels and low BMI or weight loss ≥5% experienced more irAEs (hazard ratio: 2.333; 95% confidence interval: 1.231–4.423).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;M-MDSCs in cachexic mice induced mTEC apoptosis through nitric oxide production, impairing T-cell negative selection and promoting autoimmune T-cell infiltration in","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 4","pages":"Pages 298-312"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative study of 3D MR elastography and intravoxel incoherent motion for the evaluation of hepatocellular carcinoma grade","authors":"Weimin Liu ,&nbsp;Sidong Xie ,&nbsp;Wenjie Tang ,&nbsp;Ka Zhang","doi":"10.1016/j.livres.2025.11.003","DOIUrl":"10.1016/j.livres.2025.11.003","url":null,"abstract":"<div><h3>Background and aims</h3><div>Noninvasive preoperative radiologic prediction of histologic grade—a key prognostic factor—is invaluable. We aim to compare the diagnostic values of 3D magnetic resonance elastography (MRE), intravoxel incoherent motion (IVIM), and conventional contrast-enhanced magnetic resonance imaging (cMRI) in predicting the histologic grade of hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>This institutional review board-approved retrospective study included patients who underwent MRI between December 2014 and October 2021. Sixty-eight patients with pathologically confirmed HCCs who underwent MRE, IVIM, and cMRI imaging were included in the analysis. Two radiologists measured HCC stiffness volumetrically and over a single slice, and also measured apparent diffusion coefficient (ADC), IVIM-derived parameters, and enhancement ratio (ER) on arterial phase images via cMRI. Student’s <em>t</em>-test or the Mann–Whitney <em>U</em> test was used for group comparisons. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performance.</div></div><div><h3>Results</h3><div>Histologically, fifty-three (78%) patients had well-differentiated or moderately differentiated HCCs, and fifteen (22%) patients had poorly differentiated HCCs. Both the volumetric stiffness and single-ROI tumor stiffness were significantly elevated in the poorly differentiated HCC group (<em>P</em> &lt; 0.001, <em>P</em> = 0.001), and the volumetric stiffness was a better measurement of stiffness because it had a higher ROC curve value (0.816). However, the ADC, the true diffusion coefficient (D), the pseudodiffusion coefficient (D∗), the pseudodiffusion fraction (f), and ER during the arterial phases on cMRI were not significantly different between the two groups (<em>P</em> = 0.309, 0.187, 0.440, 0.350, and 0.714, respectively).</div></div><div><h3>Conclusions</h3><div>Stiffness measured with 3D MRE may be useful for noninvasively predicting HCC histologic grade, and the volumetric measuring method achieved the highest ROC curve value, outperforming single-ROI HCC stiffness, IVIM parameters, and arterial-phase ER on cMRI.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 4","pages":"Pages 351-358"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient AAV8 delivery to the liver via isolated hepatic perfusion and analysis of hepatic lobule transduction patterns","authors":"Chao Wang ,&nbsp;Mingming Fan ,&nbsp;Jianrong Liu ,&nbsp;Xiaolu Guo ,&nbsp;Zhipeng Tan ,&nbsp;Xueying Huang ,&nbsp;Zhuoran Li ,&nbsp;Xiaomei Liu ,&nbsp;Ye Zhang ,&nbsp;Jianqi Feng ,&nbsp;Rui Fang ,&nbsp;Li Wang ,&nbsp;Qiong Ke","doi":"10.1016/j.livres.2025.04.006","DOIUrl":"10.1016/j.livres.2025.04.006","url":null,"abstract":"<div><h3>Background and aims</h3><div>Adeno-associated virus (AAV) is becoming an attractive vector due to its low toxicity and minimal immunogenicity. However, liver-targeted AAV gene therapy still faces challenges, such as low delivery efficiency and safety risks associated with high vector doses. Isolated hepatic perfusion (IHP) has been explored as a localized drug delivery method, yet its full potential in gene therapy remains under investigation. Here, we investigated the efficiency of AAV8 delivery via the IHP route and its preference for hepatic transduction.</div></div><div><h3>Methods</h3><div>The IHP route was established through surgery in rats and cynomolgus monkey, and the AAV8-dTomato solution was injected into the entire liver through the inflow tract and maintained for 10 min. One week later, liver tissues were obtained, and the dTomato fluorescence expression area fraction and intensity were analyzed.</div></div><div><h3>Results</h3><div>AAV8-dTomato delivery via the IHP resulted in over 60% dTomato-positive areas in rat liver and showed higher efficiency than the portal vein (PV) and inferior vena cava (IVC) routes at equivalent doses. In rats, AAV8-dTomato expression was primarily periportal across IHP, PV, and IVC routes, while in cynomolgus monkey, IHP delivery showed a pericentral pattern.</div></div><div><h3>Conclusions</h3><div>In this study, we found that IHP is an effective strategy for AAV8 delivery. In addition, the distribution characteristics of AAV8, when delivered in cynomolgus monkey via IHP, provide candidate vector delivery schemes for gene therapy for different types of genetic liver diseases.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 4","pages":"Pages 313-323"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatitis B virus integration and hepatocarcinogenesis","authors":"Linlin Ma ,&nbsp;Shuzhen Chen ,&nbsp;Hongyang Wang ,&nbsp;Lei Chen","doi":"10.1016/j.livres.2025.09.002","DOIUrl":"10.1016/j.livres.2025.09.002","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC), which is the predominant liver cancer type in Southeast Asia. Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide. HBV promotes HCC development through direct and indirect mechanisms. HBV DNA integrates into the host genome during the initial stages of tumorigenesis, causing insertional mutagenesis of cancer-related genes and genomic instability. Extrachromosomal circular DNA (ecDNA) is formed, which is efficiently amplified in large quantities to express viral genes and host oncogenes. Moreover, virus-associated proteins, such as the regulatory HBV X (HBx) protein and/or the modified preS/S envelope protein, alter the expression of genes associated with multiple functions in host cells. In this review, we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis. In addition to summarizing the specific mechanism of HBV-related tumorigenesis, the concerns and perspectives for future study are discussed.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 189-198"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term prognosis of recipients with pretransplant exposure to immune checkpoint inhibitors after liver transplantation for hepatocellular carcinoma: A retrospective cohort study","authors":"Li Pang ,&nbsp;Leibo Xu ,&nbsp;Zhijun Chen ,&nbsp;Yang Liu ,&nbsp;Tao Ding ,&nbsp;Yanfang Ye ,&nbsp;Xinjun Lu ,&nbsp;Guangxiang Gu ,&nbsp;Haoming Lin ,&nbsp;Wenrui Wu ,&nbsp;Kwan Man ,&nbsp;Chao Liu","doi":"10.1016/j.livres.2025.03.001","DOIUrl":"10.1016/j.livres.2025.03.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and aims&lt;/h3&gt;&lt;div&gt;Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors (ICIs) to increased allograft rejection risk after liver transplantation (LT), a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists. This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma (HCC) between June 2019 and March 2023. The recipients were categorized into ICI (&lt;em&gt;n&lt;/em&gt; = 35) and non-ICI (&lt;em&gt;n&lt;/em&gt; = 86) exposure groups based on pretransplant ICI exposure. Demographics, clinical characteristics, and short-term outcomes were compared between the cohorts. Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival. Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Recipients with or without ICI exposure exhibited comparable demographic baseline characteristics. The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups. Post-transplant infection incidence was 37.1% and 20.9% in the ICI and non-ICI groups, respectively (&lt;em&gt;P&lt;/em&gt; = 0.064). Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group (22.9% &lt;em&gt;vs.&lt;/em&gt; 5.8%, &lt;em&gt;P&lt;/em&gt; = 0.015). The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group (14.3% &lt;em&gt;vs.&lt;/em&gt; 2.3%, &lt;em&gt;P&lt;/em&gt; = 0.034). Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality, with ICI exposure being an independent risk factor for allograft rejection. In recipients with ICI exposure, a shorter interval between ICIs and LT (washout period) was significantly associated with a higher allograft rejection risk, with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival (&lt;em&gt;P&lt;/em&gt; = 0.0001). Moreover, in recipients with allograft rejection, the peripheral CD4&lt;sup&gt;+&lt;/sup&gt;/CD8&lt;sup&gt;+&lt;/sup&gt; T cell ratio was much lower in the ICI group than in the non-ICI group.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC. A ≤21-day washout period was significantly associated with allograft rejection. Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings, confirm causality, and establish standardized clinical guidelines for ICI use before transplantation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Trail registration&lt;/h3&gt;&lt;div&gt;&lt;span&gt;&lt;span&gt;Clinica","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 221-230"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvasive prediction of high-risk esophageal varices by spleen and liver stiffness measurements using sound touch elastography","authors":"Jinfen Wang ,&nbsp;Siwei Tan ,&nbsp;Ruiying Zheng ,&nbsp;Bilun Ke ,&nbsp;Bin Wu ,&nbsp;Manli Wu","doi":"10.1016/j.livres.2025.08.002","DOIUrl":"10.1016/j.livres.2025.08.002","url":null,"abstract":"<div><h3>Background and aims</h3><div>Noninvasive assessments play a crucial role in ruling out high-risk esophageal varices (HREV) in cirrhotic patients. However, the value of sound touch elastography (STE) in predicting HREV has not been comprehensively investigated. Therefore, this study aimed to establish prediction models based on liver and spleen stiffness measurements obtained by STE and provide assessment strategies and cutoff values tailored for different clinical situations.</div></div><div><h3>Methods</h3><div>This prospective study included cirrhotic patients who underwent esophagogastroduodenoscopy (EGD). Liver and spleen stiffness measurements by STE were performed within six months of EGD examination. Various prediction models and their corresponding cutoff values were established for different clinical situations, incorporating spleen diameter and laboratory parameters.</div></div><div><h3>Results</h3><div>A total of 154 cirrhotic patients were included in the study and stratified into training (<em>n</em> = 119) and validation (<em>n</em> = 35) sets. Multivariable analysis revealed platelet, spleen diameter and spleen stiffness measurement as independent predictors of HREV. The model incorporating spleen stiffness measurement, platelet, and spleen diameter demonstrated superior performance in predicting HREV, yielding an area under the receiver operating characteristic curve (AUC) of 0.878 and 0.853 in the training set and validation set, respectively. Application of this model for screening cirrhotic patients could avoid EGDs in 39.7% (27/68) and 35.3% (6/17) of patients in the training and validation sets, respectively.</div></div><div><h3>Conclusions</h3><div>Liver and spleen stiffness measurements obtained through STE are valuable for predicting HREV in cirrhotic patients. The developed prediction models and their corresponding cutoff values provide tailored solutions for various clinical situations, thereby effectively reducing the need for unnecessary endoscopies.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 231-238"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The revolutionary role of machine learning in predicting, diagnosing, and treating liver disease","authors":"Xiang-Long Huang ,&nbsp;Wen-Hao Chen ,&nbsp;Min Ding,&nbsp;Yu-Mu Song,&nbsp;Yun-Wen Zheng","doi":"10.1016/j.livres.2025.04.001","DOIUrl":"10.1016/j.livres.2025.04.001","url":null,"abstract":"","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 249-251"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionizing medicine: Exploring the breakthroughs in liver xenotransplantation","authors":"Mohamed El-Kassas ,&nbsp;Walaa Abdelhamed ,&nbsp;Khalid Al-Naamani","doi":"10.1016/j.livres.2025.08.001","DOIUrl":"10.1016/j.livres.2025.08.001","url":null,"abstract":"<div><div>The critical shortage of liver transplant donors necessitates innovative solutions, with xenotransplantation emerging as a promising alternative. Despite significant ethical, scientific, and practical challenges, recent advancements in liver xenotransplantation, particularly using pigs as donors for non-human primates (NHPs), have extended graft survival duration. However, life-threatening issues such as thrombocytopenia and coagulation disorders persist, limiting survival to under a month. Advances in genetic engineering have enabled the modification of pig genomes to match the human immune system better, targeting genes responsible for immune rejection and increasing compatibility. While these breakthroughs enhance the potential for human transplantation, the challenges of immune rejection and long-term functionality remain substantial. This review highlights recent progress in liver xenotransplantation from pigs to NHPs and explores the implications for potential human clinical application.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 199-208"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune cell LXR-β deficiency exacerbates hepatic injury and fibrosis in murine models of primary sclerosing cholangitis","authors":"Xiaohui Fang ,&nbsp;Yang Zhang ,&nbsp;Junyao Wang ,&nbsp;Yu Zhang ,&nbsp;Ziliang Ke ,&nbsp;Yiken Lin ,&nbsp;Fangyuan Cong ,&nbsp;Feng Zhang ,&nbsp;Jianhua Zhou ,&nbsp;Huiting Su ,&nbsp;Shan Cao ,&nbsp;Yulan Liu ,&nbsp;Jun Xu","doi":"10.1016/j.livres.2025.09.001","DOIUrl":"10.1016/j.livres.2025.09.001","url":null,"abstract":"<div><h3>Background and aims</h3><div>Primary sclerosing cholangitis (PSC) is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options. The mechanisms underlying the development and progression of PSCs remain unclear. Liver X receptor beta (LXR-β) is recognized to modulate lipid metabolism and immune response, but its specific involvement in the PSC has not been elucidated. Here, we explored the role and mechanism of LXR-β in PSC induced by 3, 5-diethoxycarbonyl-1, 4-dihydro-2, 4, 6-collidine (DDC).</div></div><div><h3>Methods</h3><div>CRISPR-Cas9 technology was applied to generate <em>Abcb4</em> (coding MDR2, next named as <em>Mdr2</em>), <em>Nr1h2</em> (coding LXR-β, next named as <em>Lxrβ</em>), and <em>Rag2</em> (coding RAG2) knockout mice. DDC was used to induce PSC. Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis. Flow cytometry was used to observe immune cell subsets.</div></div><div><h3>Results</h3><div>We observed a declining trend in hepatic <em>Lxrβ</em> in the PSC model. Unexpectedly, <em>Lxrβ</em> knockout failed to modulate DDC-induced PSC pathogenesis. Concomitantly, assessment of the influence of <em>Rag2</em> deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the <em>Rag2</em>^{<em>−/−</em>} DDC mice. However, <em>Lxrβ</em> depletion intensified DDC-induced PSC in the <em>Rag2</em>^{<em>−/−</em>} mice, with more abundant infiltrative inflammatory cells and more severe liver fibrosis. Compared with <em>Rag2</em>^{<em>−/−</em>} DDC mice, <em>Lxrβ</em>^{<em>−/−</em>}<em>Rag2</em>^{<em>−/−</em>} DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes. Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.</div></div><div><h3>Conclusion</h3><div>This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 239-248"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}