JHEP Reports最新文献_第8页

Lactococcus A phages predict ACLF while Enterococcus B phages predict bacterial infection in decompensated cirrhosis A乳球菌噬菌体预测ACLF，而B肠球菌噬菌体预测失代偿肝硬化的细菌感染

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-10 DOI: 10.1016/j.jhepr.2025.101622

Lore Van Espen , Maximilian Joseph Brol , Lila Close , Robert Schierwagen , Wenyi Gu , Marisa I. Keller , Boglarka Balogh , Anthony Fullam , Lander De Coninck , Tomohiro Nakamura , Michael Kuhn , Peer Bork , Wim Laleman , Jasmohan S. Bajaj , Maria Papp , Bernd Schnabl , Jonel Trebicka , Jelle Matthijnssens , MICROB-PREDICT

Background & Aims

As portal hypertension progresses in cirrhosis, bacterial translocation across a compromised gut barrier leads to endotoxemia, systemic inflammation and immune dysfunction. Gut phages play a key role in these processes by influencing bacteria-host interactions. This study explores the role of the human gut virome in acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF).

Methods

The fecal virome was longitudinally assessed by metagenomic sequencing in two independent cohorts: 93 patients (292 samples) with acute decompensation or ACLF from the PREDICT study, and 94 patients (94 samples) with decompensated cirrhosis undergoing TIPS (transjugular intrahepatic portosystemic shunt) surgery collected in a tertiary care setting. Besides descriptive analysis, phages were grouped according to their predicted bacterial host and lifestyle, and associated with clinical parameters.

Results

Phage alpha-diversity was higher in patients with ACLF and correlated with ACLF severity. In the absence of ACLF, the phageome was dominated by virulent phages, but in ACLF, temperate phages became more prevalent. Genus-level analysis showed that phageomes were highly patient-specific. Lactococcus A phages were the only phage-host group predicting ACLF development (odds ratio [OR] = 14; Fisher test p = 0.0129). Enterococcus B phages (OR = 14.7; p = 0.0015; adj. p = 0.037) and their bacterial hosts (OR = 2.8; p = 0.020) were significantly more prevalent in cases of proven systemic bacterial infection. The presence of both phage families was linked to increased 90-day mortality rates.

Conclusion

ACLF is characterized by increased fecal virome diversity and a shift from virulent toward temperate phages at disease onset. Our study links Lactococcus A phages to ACLF development, and Enterococcus B phages to bacterial infection, while both are associated with increased 90-day mortality.

Clinical trial number

NCT03056612.

Impact and implications

The human gut virome is a poorly investigated part of the human gut microbiome, especially in the context of decompensated cirrhosis and acute-on-chronic liver failure. This study identified two phage groups (Lactococcus A phages and Enterococcus B phages) with particular prognostic value. In the future, virome analysis of fecal samples could be useful for patient stratification in clinical practice.

背景和目的随着肝硬化门静脉高压的进展，细菌易位通过受损的肠道屏障导致内毒素血症、全身炎症和免疫功能障碍。肠道噬菌体通过影响细菌-宿主相互作用在这些过程中发挥关键作用。本研究探讨了人类肠道病毒在肝硬化和急性慢性肝衰竭（ACLF）急性失代偿中的作用。方法通过宏基因组测序对两个独立队列的粪便病毒组进行纵向评估：来自PREDICT研究的93例（292份样本）急性失代偿或ACLF患者，以及来自三级医疗机构的94例（94份样本）失代偿肝硬化患者接受TIPS（经颈内肝门系统分流术）手术。除描述性分析外，根据噬菌体预测的细菌宿主和生活方式进行分组，并与临床参数相关联。结果ACLF患者肝细胞α多样性较高，且与ACLF严重程度相关。在没有ACLF的情况下，噬菌体以毒性噬菌体为主，但在ACLF中，温带噬菌体更为普遍。属水平分析表明，噬菌体具有高度的患者特异性。乳球菌A噬菌体是唯一预测ACLF发展的噬菌体-宿主组（优势比[OR] = 14； Fisher检验p = 0.0129）。B肠球菌噬菌体（OR = 14.7; p = 0.0015; adj. p = 0.037）及其细菌宿主（OR = 2.8; p = 0.020）在已证实的全身性细菌感染病例中更为普遍。这两个噬菌体家族的存在与90天死亡率增加有关。结论aclf的特点是在发病时粪便病毒多样性增加，从毒性噬菌体向温带噬菌体转变。我们的研究将A乳球菌噬菌体与ACLF的发展联系起来，将B肠球菌噬菌体与细菌感染联系起来，而两者都与90天死亡率增加有关。临床试验编号：bernct03056612。影响和意义人类肠道病毒是人类肠道微生物组中研究较少的一部分，特别是在失代偿肝硬化和急性慢性肝衰竭的背景下。本研究发现两种噬菌体（乳球菌A噬菌体和肠球菌B噬菌体）具有特殊的预后价值。在未来，粪便样本的病毒组分析可用于临床实践中的患者分层。

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引用次数: 0

Challenges in the diagnosis and treatment of genetic cholestasis in adults 成人遗传性胆汁淤积症诊断和治疗的挑战

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101625

Richard J. Thompson , Silvia Vilarinho , Rosa Miquel , Verena Keitel

Disorders of bile formation and bile flow along the intra- and extrahepatic bile ducts are summarised under the term cholestasis. Clinically, conditions resulting in retention of biliary constituents such as bile acids within hepatocytes (termed primary cholestasis) need to be distinguished from diseases characterised by bile duct injury (termed cholangiopathies). Some cholangiopathies may also cause retention of biliary constituents within hepatocytes, resulting in secondary cholestasis. Genetic variants in a multitude of genes can contribute to the development of both primary cholestasis and cholangiopathies. Assessing the contribution of identified genetic variants to the clinical presentation in adults is complicated by factors such as environmental exposure, comorbidities, and medication intake. The diagnostic workup in adults with cholestasis should first consider common causes of primary cholestasis and cholangiopathies. If the aetiology remains unclear, liver histology and/or genetic testing should be pursued. Until recently, treatment for these conditions was largely supportive. However pharmacological interruption of the enterohepatic circulation of bile acids now offers the possibility of more specific intervention. Moreover, for those conditions in which the bile duct epithelium is the main site of injury, ursodeoxycholic acid remains essential. Multidisciplinary case discussions can help facilitate diagnosis and guide management.

胆汁形成和胆汁沿肝内和肝外胆管流动的紊乱在胆汁淤积症下被总结。临床上，导致胆道成分（如肝细胞内胆汁酸）潴留的疾病（称为原发性胆汁淤积）需要与以胆管损伤为特征的疾病（称为胆管病）区分开来。一些胆管疾病也可能引起肝细胞内胆道成分潴留，导致继发性胆汁淤积。多种基因的遗传变异可导致原发性胆汁淤积症和胆管病的发生。由于环境暴露、合并症和药物摄入等因素，评估已确定的遗传变异对成人临床表现的影响是复杂的。成人胆汁淤积症的诊断应首先考虑原发性胆汁淤积症和胆管病变的常见原因。如果病因不明，应进行肝脏组织学和/或基因检测。直到最近，对这些疾病的治疗在很大程度上还是支持性的。然而，胆汁酸的肠肝循环的药理学中断现在提供了更具体的干预的可能性。此外，对于以胆管上皮为主要损伤部位的情况，熊去氧胆酸仍然是必需的。多学科病例讨论有助于促进诊断和指导管理。

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引用次数: 0

From model to man: Understanding Tregs' dual role in MASLD 从模型到人：理解Tregs在MASLD中的双重作用

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101619

Janine Dywicki , Laura Elisa Buitrago-Molina , Anna K. Baumann , Ana C. Davalos-Misslitz , Celina M. Hendriks , Katharina L. Hupa-Breier , Maren Lieber , Jerome Schlue , Matthias Blüher , Heike Bantel , Christine S. Falk , Christian Koenecke , Freya Wellhöner , Benjamin Heidrich , Michael P. Manns , Fatih Noyan , Heiner Wedemeyer , Richard Taubert , Elmar Jaeckel , Matthias Hardtke-Wolenski

Background & Aims

Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) affects around 30% of the world's population and is often associated with metabolic conditions such as obesity, diabetes and hypertension. Approximately 10-20% of metabolic dysfunction-associated steatotic liver disease cases progress to metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of liver cancer. While intrahepatic immune responses involving CD4+ and CD8+ T cells are potential therapeutic targets, their role in the pathogenesis of MASH is not fully understood. Regulatory T cells (Tregs), whose involvement has been controversial, require further investigation.

Methods

In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and Rag2-deficient C57BL/6 mice, supplemented with human liver samples.

Results

Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.

Conclusions

The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (T_H17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.

Impact and implications

Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3⁺ T regulatory cells (Tregs) and CD8⁺ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.

背景与目的代谢功能障碍相关的脂肪变性肝病（MASLD）影响着世界上约30%的人口，通常与代谢疾病如肥胖、糖尿病和高血压有关。大约10-20%的代谢功能障碍相关脂肪性肝病病例进展为代谢功能障碍相关脂肪性肝炎（MASH），这显著增加了肝癌的风险。虽然涉及CD4+和CD8+ T细胞的肝内免疫反应是潜在的治疗靶点，但它们在MASH发病机制中的作用尚不完全清楚。调节性T细胞（Tregs）的参与一直存在争议，需要进一步研究。方法本研究采用高脂/高碳水化合物饮食（HF-HCD）模型，研究了适应性免疫对野生型和rag2缺陷型C57BL/6小鼠MASH的影响，并补充了人肝样本。结果HF-HCD诱导葡萄糖耐受不良和MASH，不依赖于适应性免疫。令人惊讶的是，HF-HCD增加了肝内Treg数量和Treg/Teff比值，但没有减轻疾病；相反，这种增加与更严重的疾病有关。随着代谢性炎症的进展，treg表达IL-17的比例也增加，这与更严重的肝脏病理相关。结论观察到Treg的扩增和Treg/Teff比例的增加并不能预防MASH，但在小鼠和人类中与更严重的疾病相关，这与向产生il -17 （th17倾斜）细胞的促炎转移一致。这些发现强调了适应性免疫在MASH进展中的复杂作用，并为未来的免疫调节治疗提供了潜在的靶点。影响和意义饮食诱导的脂肪性肝炎可以在没有适应性免疫的情况下发展，然而表达il - 17a的Foxp3+ T调节细胞（Tregs）和CD8+ T细胞显著放大肝细胞损伤和纤维化。通过分离初始（巨噬细胞驱动）和放大（适应性）免疫信号，我们的研究改进了当前的致病模型，并为肝病学家和免疫学家提供了特定阶段的治疗靶点。对于临床医生和试验设计者来说，数据表明稳定Treg或选择性抑制促炎t细胞亚群可以补充代谢干预与代谢功能障碍相关的脂肪变性肝病/脂肪性肝炎，而不加选择地扩大Treg可能适得其反。由于结论是从小鼠模型中得出的，因此将其转化为人类将需要在患者来源的组织和非侵入性免疫生物标志物中进行验证。

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引用次数: 0

Binge drinking acutely induces hepatic steatosis which is readily reversible: A real-world observational study in healthy adults 酗酒急性诱导肝脂肪变性是容易可逆的：一项现实世界的观察研究在健康成人

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101623

Kristoffer Kjærgaard , Jeppe Mygind Yeoman , Peter Lykke Eriksen , Anne Catrine Daugaard Mikkelsen , Emilie Eifer Møller , Ann-Sophie Frees Wietz , Andressa de Zawadzki , Lars Christian Gormsen , Sara Heebøll , Hendrik Vilstrup , Karen Louise Thomsen

Background & Aims

Binge drinking is a common pattern of alcohol intake often considered particularly harmful. However, its immediate effects on the development of hepatic steatosis and early alcohol-related liver injury are not well established. This study aimed to investigate the acute effects of binge drinking on the liver and its reversibility in healthy individuals.

Methods

Healthy adults were studied in a real-world setting before, the day after, and 10 days after attending a 3-day festival. The participants were alcohol abstinent 1 week prior to the first visit and between the last two visits. Each visit included liver MRI-proton density fat fraction and elastography, and blood tests. Alcohol and food intake were self-reported during the festival, and blood alcohol concentration was measured once daily.

Results

Fifteen participants (9 male, 6 female) aged 36 ± 5 years with a BMI of 23.2 ± 2.7 kg/m² completed the study. They consumed 186 ± 56 g of alcohol per day resulting in a 2.5-fold increase in hepatic fat fraction from 1.9% (IQR 1.6%-2.5%) to 4.6% (IQR 2.4%-5.7%), p <0.0001. Six participants (40%) developed steatosis; compared to those without steatosis, they had higher baseline BMI, triglycerides and glucagon, and lower free fatty acids, while there was no difference in alcohol or energy consumption. Binge drinking also increased liver stiffness and triglycerides, while LDL-cholesterol decreased. After 10 days of abstinence, all outcome measures were normalised.

Conclusions

Three days of recreational binge drinking increased liver fat content and stiffness in most participants. This early consequence of excessive alcohol intake was resolved after 10 days of abstinence, suggesting that the acute hepatic effects of binge drinking are readily reversible if followed by short-term abstinence.

Impact and implications

Binge drinking is considered a high-risk pattern of alcohol intake associated with various health hazards, yet its immediate effects on the liver are not well understood. This study provides direct real-world evidence that one episode of binge drinking (3 days) can acutely induce hepatic steatosis in healthy individuals, particularly those with subclinical metabolic dysfunction. Importantly, all consequences of binge drinking were normalised following 10 days of alcohol abstinence. These findings offer timely insight into the health risks of recreational binge drinking and contribute knowledge with potential implications for public health messaging and recommendations, clinical guidance, and alcohol policies.

背景和目的酗酒是一种常见的酒精摄入模式，通常被认为是特别有害的。然而，它对肝脂肪变性和早期酒精相关肝损伤的直接影响尚未得到很好的证实。本研究旨在探讨酗酒对健康个体肝脏的急性影响及其可逆性。方法在现实环境中对健康成人参加为期3天的节日活动前、后1天和后10天进行研究。参与者在第一次访问前1周和最后两次访问之间戒酒。每次访问包括肝脏mri质子密度脂肪分数和弹性成像，以及血液检查。在节日期间，酒精和食物摄入量是自我报告的，血液酒精浓度每天测量一次。结果15名参与者（男9名，女6名）完成研究，年龄36±5岁，BMI为23.2±2.7 kg/m2。他们每天摄入186±56克酒精，导致肝脏脂肪含量从1.9% （IQR 1.6%-2.5%）增加2.5倍至4.6% (IQR 2.4%-5.7%), p <0.0001。6名参与者（40%）发生脂肪变性；与没有脂肪变性的人相比，他们的基线BMI、甘油三酯和胰高血糖素更高，游离脂肪酸更低，而酒精和能量消耗没有差异。酗酒还会增加肝脏硬度和甘油三酯，同时降低低密度脂蛋白胆固醇。禁欲10天后，所有结果指标归一化。结论3天的娱乐性狂饮增加了大多数参与者的肝脏脂肪含量和硬度。过量饮酒的早期后果在戒酒10天后就消失了，这表明，如果在短期戒酒后，酗酒对肝脏的急性影响很容易逆转。影响和启示酗酒被认为是一种高风险的酒精摄入模式，与各种健康危害有关，但其对肝脏的直接影响尚不清楚。这项研究提供了直接的现实证据，证明一次狂饮（3天）可以急性诱导健康个体的肝脂肪变性，特别是那些有亚临床代谢功能障碍的人。重要的是，在戒酒10天后，酗酒的所有后果都恢复正常。这些发现及时地揭示了娱乐性狂饮的健康风险，并为公共卫生信息和建议、临床指导和酒精政策提供了潜在的启示。

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引用次数: 0

Epidemiology, clinical, molecular features, and prognosis of early-onset biliary tract cancer: A systematic review and meta-analysis 早发性胆道癌的流行病学、临床、分子特征和预后：系统回顾和荟萃分析

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101613

Erman Akkus , Antonella Cammarota , Laura Izquierdo-Sanchez , Jesus M. Banales , Alejandro Forner , Ana Lleo , Rocio I.R. Macias , Angela Lamarca , Mohamed Bouattour

<div><h3>Background & Aims</h3><div>Early-onset gastrointestinal cancers represent a growing global health concern. Among these, early-onset biliary tract cancer (EO-BTC) remains relatively understudied. In this systematic review, we synthesize current evidence for EO-BTC.</div></div><div><h3>Methods</h3><div>A comprehensive systematic literature search was performed across multiple databases. Original studies investigating epidemiology, risk factors, clinical presentation, pathological and/or molecular features, treatment, and prognosis of EO-BTC were included and synthesized. Meta-analyses were performed using the Mantel–Haenszel and generic inverse variance methods with random-effects models.</div></div><div><h3>Results</h3><div>In total, 32 studies were included. EO-BTC incidence varied by anatomical subtype, with a notable increase in early-onset intrahepatic cholangiocarcinoma. Disparities in ethnicity and socioeconomic status were apparent between younger and older patients. Clinically, the disease was often diagnosed at a more advanced stage in younger patients (for stage IV, odds ratio [OR], 1.31; 95% CI, 1.19–1.43; <em>p</em> <0.001; <em>I</em><sup><em>2</em></sup>, 62%) and was associated with a higher prevalence of intrahepatic cholangiocarcinoma (OR, 1.41; 95% CI, 1.23–1.61; <em>p</em> <0.001; <em>I</em><sup><em>2</em></sup>, 49%). <em>FGFR2</em> fusions were significantly more common in early-onset cases (OR, 2.81; 95% CI, 2.31–3.64; <em>p</em> <0.001; <em>I</em><sup><em>2</em></sup>, 0%). Younger patients had fewer comorbidities and more frequently received curative-intent local and systemic therapies (surgery: OR, 1.38; 95% CI, 1.22–1.57; <em>p</em> <0.001; <em>I</em><sup><em>2</em></sup>, 85%). Prognostic data were heterogeneous; however, pooled analysis suggested a trend to improved OS in patients with early-onset disease (unadjusted hazard ratio [HR], 0.84; 95% CI, 0.75–0.93; <em>p</em> = 0.001; <em>I</em><sup><em>2</em></sup>, 81%); adjusted HR, 0.78; 95% CI, 0.66–0.94; <em>p</em> = 0.007; <em>I</em><sup><em>2</em></sup>, 91%).</div></div><div><h3>Conclusions</h3><div>EO-BTC represents a clinically and molecularly distinct subset within biliary tract cancers, with emerging epidemiological patterns, a higher prevalence of actionable molecular alterations, and differences in treatment allocation. Further prospective and age-stratified studies are needed to guide age-adapted detection and therapeutic strategies.</div></div><div><h3>PROSPERO ID</h3><div>CRD420251039039.</div></div><div><h3>Impact and implications</h3><div>This systematic review highlights that EO-BTC exhibits different epidemiological and molecular patterns compared with later-onset disease, including a higher prevalence of intrahepatic subtypes and greater frequency of targetable alterations, such as <em>FGFR2</em> fusions. These findings underscore the importance of incorporating routine molecular profiling and the integration of stratified manag

背景：早发性胃肠道癌症已成为全球日益关注的健康问题。其中，早发性胆道癌（EO-BTC）的研究相对较少。在这篇系统综述中，我们综合了目前EO-BTC的证据。方法对多个数据库进行全面系统的文献检索。对EO-BTC的流行病学、危险因素、临床表现、病理和/或分子特征、治疗和预后等方面的原始研究进行了纳入和综合。采用随机效应模型的Mantel-Haenszel和通用逆方差方法进行meta分析。结果共纳入32项研究。EO-BTC的发病率因解剖亚型而异，在早发性肝内胆管癌中显著增加。在种族和社会经济地位的差异在年轻和老年患者之间是明显的。临床上，该病通常在较年轻患者的较晚期被诊断出来（IV期，优势比[OR]为1.31；95% CI为1.19-1.43;p <0.001; I2, 62%），并且与较高的肝内胆管癌患病率相关（OR为1.41；95% CI为1.23-1.61;p <0.001; I2, 49%）。FGFR2融合在早发病例中更为常见（OR, 2.81; 95% CI, 2.31-3.64; p <0.001; i2,0%）。年轻患者的合并症较少，更频繁地接受治疗目的的局部和全身治疗（手术：OR， 1.38; 95% CI, 1.22-1.57; p <0.001; I2, 85%）。预后数据不一致；然而，合并分析显示早发性疾病患者有改善OS的趋势（未调整风险比[HR]为0.84；95% CI为0.75-0.93;p = 0.001； I2为81%）；调整后的HR为0.78；95% ci, 0.66-0.94；P = 0.007；I2, 91%)。结论seo - btc是胆道肿瘤中一个临床和分子上独特的亚群，具有新兴的流行病学模式、更高的可操作分子改变发生率和治疗分配的差异。需要进一步的前瞻性和年龄分层研究来指导适合年龄的检测和治疗策略。普洛斯彼罗IDCRD420251039039。影响和意义本系统综述强调，与晚发性疾病相比，EO-BTC表现出不同的流行病学和分子模式，包括更高的肝内亚型患病率和更高的靶向改变频率，如FGFR2融合。这些发现强调了将常规分子谱分析和分层管理途径整合到临床实践中的重要性。从公共卫生的角度来看，EO-BTC发病率的上升，特别是在没有传统风险因素的个人中，突出表明迫切需要提高认识并制定适应风险的早期发现战略。有趣的是，年轻的患者更有可能接受手术切除，即使是那些患有晚期疾病的患者。这一趋势可能反映了在这一人群中更大的临床意愿追求积极的方法，可能受到更好的表现状态和更少的合并症的影响。然而，当预期的肿瘤获益有限时，它也强调了谨慎选择患者以避免不必要的手术并发症的必要性。总的来说，这些发现强调了前瞻性、年龄分层研究的必要性，以更好地定义预后模型，并指导针对这一独特患者群体的个性化治疗方法。

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引用次数: 0

Comparative effectiveness of antidiabetic therapies on hepatic decompensation in patients with type 2 diabetes: A target trial emulation 抗糖尿病治疗对2型糖尿病患者肝功能失代偿的比较效果：一项目标试验模拟

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101624

Jonggi Choi , Ana Verma , Vy H. Nguyen , Eric Przybyszewski , Jiunn Song , Allison Carroll , Megan Michta , Erik Almazan , Tracey G. Simon , Raymond T. Chung

<div><h3>Background & Aims</h3><div>The comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.</div></div><div><h3>Methods</h3><div>We conducted a retrospective new-user cohort study emulating a target trial using electronic health records from the Mass General Brigham health system (USA) between January 2012 and June 2024. Adults with T2DM who newly initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), or sulfonylureas were included. Propensity scores were estimated using prespecified clinical and high-dimensional covariates, and overlap weighting was applied to achieve covariate balance.</div></div><div><h3>Results</h3><div>Among 38,524 eligible patients, 12,344 initiated GLP-1RAs, 5,233 SGLT2is, 3,717 DPP4is, and 17,230 sulfonylureas. Over a median follow-up of 3.1 years, 1,743 hepatic decompensation events occurred. In the intention-to-treat analysis, GLP-1RAs (hazard ratio [HR] 0.58, 95% CI 0.38–0.88) and SGLT2is (HR 0.65, 95% CI 0.43–0.98) were associated with significantly lower risk compared with sulfonylureas. Pairwise analyses also showed reduced risk with GLP-1RAs (HR 0.59, 95% CI 0.39–0.89) and SGLT2is (HR 0.66, 95% CI 0.43–1.00) compared with DPP4is, with no significant difference between GLP-1RAs and SGLT2is. In the per-protocol analysis (1,151 events), GLP-1RAs (HR 0.43, 95% CI 0.22–0.82) remained strongly protective, while SGLT2is showed a trend toward reduced risk (HR 0.61, 95% CI 0.33–1.12). Sensitivity analyses excluding early events or using alternative weighting approaches produced consistent results.</div></div><div><h3>Conclusion</h3><div>In patients with T2DM, initiation of GLP-1RAs or SGLT2is was associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and DPP4is. These findings support their preferential use in clinical practice.</div></div><div><h3>Impact and implications</h3><div>This study provides robust real-world evidence on the comparative effectiveness of four major antidiabetic drug classes in reducing hepatic decompensation among patients with type 2 diabetes mellitus. Our findings suggest that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors, supporting their preferential use in patients with coexisting diabetes and liver disease risk. These results are particularly relevant for clinicians managing patients with type 2 diabetes who may have unrecognized metabolic dysfunction-associated steatotic liver disease or other chronic liver diseases. In practice, these findings can help guide therapeutic decision-making by integrating liver-related outcomes into antidiabetic drug selection. However, future pros

背景和目的降糖治疗对2型糖尿病（T2DM）患者肝脏预后的比较效果尚未得到很好的证实。方法采用2012年1月至2024年6月美国麻省总医院布里格姆卫生系统的电子健康记录，进行了一项回顾性新用户队列研究，模拟了一项目标试验。新开始使用钠-葡萄糖共转运体-2抑制剂（SGLT2is）、胰高血糖素样肽-1受体激动剂（GLP-1RAs）、二肽基肽酶-4抑制剂（DPP4is）或磺脲类药物的T2DM患者纳入研究。使用预先指定的临床和高维协变量估计倾向得分，并应用重叠加权来实现协变量平衡。在38,524例符合条件的患者中，12,344例启动GLP-1RAs， 5,233例启动SGLT2is， 3,717例启动dpp4, 17,230例启动磺脲类药物。在中位随访3.1年期间，发生了1743例肝功能失代偿事件。在意向治疗分析中，与磺脲类药物相比，GLP-1RAs（风险比[HR] 0.58, 95% CI 0.38-0.88）和SGLT2is（风险比[HR] 0.65, 95% CI 0.43-0.98）的风险显著降低。两两分析还显示，与dpp4相比，GLP-1RAs （HR 0.59, 95% CI 0.39-0.89）和SGLT2is （HR 0.66, 95% CI 0.43-1.00）的风险降低，GLP-1RAs和SGLT2is之间无显著差异。在每个方案分析（1151个事件）中，GLP-1RAs （HR 0.43, 95% CI 0.22-0.82）仍然具有很强的保护作用，而SGLT2is显示出降低风险的趋势（HR 0.61, 95% CI 0.33-1.12）。排除早期事件或使用替代加权方法的敏感性分析产生一致的结果。结论在T2DM患者中，与磺脲类药物和dpp4相比，GLP-1RAs或SGLT2is的启动与肝代偿失代偿的风险显著降低相关。这些发现支持了它们在临床实践中的优先使用。影响和意义本研究为四种主要抗糖尿病药物在减少2型糖尿病患者肝功能失代偿方面的比较有效性提供了强有力的现实证据。我们的研究结果表明，与磺脲类药物和二肽基肽酶-4抑制剂相比，胰高血糖素样肽-1受体激动剂和钠-葡萄糖共转运蛋白-2抑制剂与肝脏失代偿风险显著降低相关，支持它们优先用于糖尿病和肝脏疾病风险并存的患者。这些结果对临床医生管理2型糖尿病患者特别重要，这些患者可能患有未被识别的代谢功能障碍相关的脂肪变性肝病或其他慢性肝病。实际上，这些发现可以通过将肝脏相关结果整合到抗糖尿病药物选择中来帮助指导治疗决策。然而，未来的前瞻性研究需要验证这些发现，并阐明观察到的益处背后的机制。

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引用次数: 0

Liver fibrosis is associated with clinical and economic burden of cardiovascular disease in MASH 肝纤维化与MASH患者心血管疾病的临床和经济负担相关

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101621

Kathleen Corey , Anurag Mehta , Kamal Kant Mangla , Abhishek Shankar Chandramouli , Ahsan Shoeb , Niels Krarup , Margarida Augusto , Katrine Grau , Sharat Varma , Elisabetta Bugianesi

Background & Aims

The clinical and economic burden of cardiovascular (CV) disease (CVD) in patients with metabolic dysfunction-associated steatohepatitis (MASH) is incompletely understood. The unCoVer–MASH cohort study aimed to assess the association of CVD-related burden with fibrosis (Fibrosis-4 index [FIB-4]) in patients with MASH in a real-world US database.

Methods

Adult patients with an ICD code for non-alcoholic steatohepatitis (NASH; October 2015–June 2022) were included if they had ≥1 FIB-4 measurement calculated from data obtained within 180 days before or 30 days after the NASH diagnosis (index date), ≥12 months of data prior to the index date (baseline period), and no diagnostic evidence of cirrhosis at baseline. FIB-4 categories were low (<1.30), intermediate (1.30–2.67), and high (>2.67). Risk of CV events was assessed during follow-up, and hazard ratios (HRs) were calculated using Cox proportional hazards models. CVD-related economic burden and resource utilization were also assessed.

Results

Of 715 patients included at baseline,102 had high, 201 had intermediate, and 412 had low FIB-4 scores. The risk of any CV event was significantly greater in the high (HR 3.44; 95% CI 2.22–5.34; p <0.001) and intermediate (HR 1.53; 95% CI 1.02–2.31; p = 0.040) FIB-4 groups compared with the low group. The risk remained significant after adjustment for CV risk factors in patients with high vs. low FIB-4 (HR 2.026; 95% CI 1.215–3.380; p = 0.007). Additionally, CV-related healthcare resource utilization and CV-related costs increased with higher FIB-4 scores.

Conclusions

Patients with MASH and high baseline FIB-4 scores were at an increased risk of CV events and had higher CV-related healthcare costs and resource utilization.

Impact and implications

Studies specifically evaluating the clinical and economic burden of CVD in patients with MASH, without diagnostic evidence of cirrhosis, are lacking. In the current study, the clinical and economic burden of CVD in such patients was associated with baseline liver fibrosis severity, as assessed using baseline FIB-4 score, indicating a higher CV burden among patients with higher fibrosis severity. These results are important for both clinicians and payers, as they illustrate that tackling the CV-related burden in MASH is likely to have an appreciable impact on both clinical and economic outcomes.

背景和目的代谢功能障碍相关脂肪性肝炎（MASH）患者心血管（CV）疾病（CVD）的临床和经济负担尚不完全清楚。unCoVer-MASH队列研究旨在评估美国真实数据库中MASH患者cvd相关负担与纤维化的关系（纤维化-4指数[FIB-4]）。方法纳入ICD编码为非酒精性脂肪性肝炎（NASH， 2015年10月- 2022年6月）的成年患者，如果他们在NASH诊断前180天或诊断后30天（索引日期），在索引日期（基线期）之前≥12个月的数据中获得≥1项FIB-4测量，并且基线时没有肝硬化的诊断证据。FIB-4分低（> 1.30）、中（>2.67）、高（>2.67）。随访期间评估心血管事件的风险，并使用Cox比例风险模型计算风险比（hr）。还评估了与心血管病有关的经济负担和资源利用情况。结果在基线时纳入的715例患者中，102例FIB-4评分高，201例为中等，412例为低。与低FIB-4组相比，高FIB-4组（HR 3.44; 95% CI 2.22-5.34; p <0.001）和中FIB-4组（HR 1.53; 95% CI 1.02-2.31; p = 0.040）发生CV事件的风险显著更高。在调整了高FIB-4和低FIB-4患者的CV危险因素后，风险仍然显著（HR 2.026; 95% CI 1.215-3.380; p = 0.007）。此外，cv相关的医疗资源利用率和cv相关成本随着FIB-4得分的增加而增加。结论：MASH患者和基线FIB-4评分高的患者发生CV事件的风险增加，CV相关的医疗费用和资源利用率也较高。影响和意义目前缺乏专门评估MASH患者CVD的临床和经济负担的研究，没有肝硬化的诊断证据。在目前的研究中，这些患者的CVD临床和经济负担与基线肝纤维化严重程度相关，使用基线FIB-4评分进行评估，表明纤维化严重程度越高的患者的CV负担越高。这些结果对临床医生和支付方都很重要，因为它们表明，在MASH中解决cv相关负担可能对临床和经济结果产生可观的影响。

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引用次数: 0

Transcriptome of monocytes from liver, brain and bone marrow reveals organ-specific features in aging and alcohol misuse 来自肝脏、大脑和骨髓的单核细胞转录组揭示了衰老和酒精滥用的器官特异性特征

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101603

Martí Ortega-Ribera , Radhika Joshi , Sergi Guixé-Muntet , Veronika Brezani , Prashanth Thevkar Nagesh , Viliam Brezani , Arman Patel , Yuan Zhuang , Mrigya Babuta , Jordi Gracia-Sancho , Gyongyi Szabo

Background & Aims

Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear.

Methods

We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20–24-month-old) female C57BL/6N mice (n = 4–6 per group). Statistical significance was determined using two-way ANOVA.

Results

MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways.

Conclusion

Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse.

Impact and implications

Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk.

背景&；目的衰老和酒精滥用分别改变单核细胞（MO）和巨噬细胞（MØ）功能，导致抗菌反应受损。然而，酒精滥用如何导致衰老过程中MO/MØ功能受损仍不清楚。方法比较幼龄（3月龄）和老龄（20 - 24月龄）雌性C57BL/6N小鼠（每组n = 4-6只）酒精调节生态位（肝脏、脑和骨髓[BM]）中MOs和MØs的转录组。采用双因素方差分析确定统计学显著性。结果smo /MØ转录组对衰老和酒精表现出独特的器官特异性反应。衰老引发了病原体反应途径的普遍失调，而酒精滥用通常会抑制老年人群中的IFN信号传导。我们对利用配体-受体相互作用进行的细胞间交流的研究表明，BM MOs的交流能力最差，而肝脏MØs的交流能力最强。酒精滥用特别增加了MO/MØ在衰老中的沟通。我们还发现并验证了衰老过程中酒精滥用中驱动器官间MO/MØ串音的特定途径，包括从肝脏到小胶质细胞的APOE-TREM2信号以及NRXN2和SPP1途径。我们的研究结果为MO/MØ转录组的异质性提供了独特的见解，并定义了衰老和酒精滥用期间BM、肝脏和大脑之间的器官间串音。影响和启示衰老和酒精滥用与免疫功能障碍、全身炎症和先天免疫反应改变有关。在这里，我们在转录组水平上检测了酒精暴露下年轻和年老小鼠肝脏、大脑和骨髓中的单核/巨噬细胞反应。我们观察到，衰老和酒精主要引起基因表达的器官特异性变化，不同组织中单核细胞/巨噬细胞群体之间的重叠最小。然而，衰老通常上调病原体反应途径，而酒精滥用抑制干扰素信号传导。我们还通过分析不同单核细胞/巨噬细胞群体中的配体受体表达来评估细胞间的通讯，并从引导器官间信号传导的主要途径中鉴定出候选分子（APOE, TREM2, NRXN2, SPP1），特别是在衰老和酒精滥用中。我们的研究结果产生了一个独特的知识库，并为衰老和酒精如何影响组织特异性单核细胞/巨噬细胞及其串扰提供了新的见解。

{"title":"Transcriptome of monocytes from liver, brain and bone marrow reveals organ-specific features in aging and alcohol misuse","authors":"Martí Ortega-Ribera , Radhika Joshi , Sergi Guixé-Muntet , Veronika Brezani , Prashanth Thevkar Nagesh , Viliam Brezani , Arman Patel , Yuan Zhuang , Mrigya Babuta , Jordi Gracia-Sancho , Gyongyi Szabo","doi":"10.1016/j.jhepr.2025.101603","DOIUrl":"10.1016/j.jhepr.2025.101603","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear.</div></div><div><h3>Methods</h3><div>We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20–24-month-old) female C57BL/6N mice (n = 4–6 per group). Statistical significance was determined using two-way ANOVA.</div></div><div><h3>Results</h3><div>MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways.</div></div><div><h3>Conclusion</h3><div>Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse.</div></div><div><h3>Impact and implications</h3><div>Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101603"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Viral sequence analysis of chronic hepatitis B patients treated with the siRNA JNJ-73763989 in phase II clinical trials siRNA JNJ-73763989治疗慢性乙型肝炎II期临床试验的病毒序列分析

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.jhepr.2025.101618

Thierry Verbinnen , Erkki Lathouwers , John Jezorwski , Michael Biermer , Ilse Augustyns , Craig Grant , Kosh Agarwal , Man-Fung Yuen , Sandra De Meyer , Oliver Lenz

<div><h3>Background & Aims</h3><div>JNJ-73763989 (JNJ-3989) is a small-interfering RNA composed of two triggers targeting the HBsAg and HBx protein open reading frame, designed to target all HBV RNAs for degradation. JNJ-3989 + nucleos(t)ide analogue (NA) treatment dose-dependently reduced chronic hepatitis B (CHB) viral antigens. Viral sequence changes in the JNJ-3989 S-/X-trigger target regions were evaluated at baseline, on-treatment, and in patients with virologic relapse (VR) after discontinuation of all treatment in REEF-1 (NCT03982186) and REEF-2 (NCT0412954) studies.</div></div><div><h3>Methods</h3><div>HBV DNA/RNA was extracted from plasma samples, and the HBV genome was sequenced using next-generation sequencing. Nucleotide variants were defined as changes <em>vs.</em> the universal HBV reference sequence (read frequency >15%).</div></div><div><h3>Results</h3><div>Baseline polymorphisms in the JNJ-3989 target region complementary to positions 2-18 of the S-/X-trigger were present in 10.1% and 2.4% of not currently treated patients, respectively, with no relevant impact on JNJ-3989-induced HBsAg decline. Variants at X-trigger target region positions of interest (POI) were more frequently observed off treatment in JNJ-3989-treated virologically suppressed (VS) patients with VR <em>vs</em>. NA-control arm VS patients with VR (55.8% <em>vs</em>. 5.7%, respectively). Variants at S-trigger POI were observed off treatment in 32.1% and 19.4% of JNJ-3989- and NA-control treated VS patients with VR, respectively. Off-treatment HBsAg kinetics did not differ between JNJ-3989-treated patients with and without variants in S-/X-trigger target POI during VR.</div></div><div><h3>Conclusion</h3><div>Baseline sequence polymorphisms did not impact JNJ-3989 treatment response. JNJ-3989-treated patients who experienced VR post-treatment had variants in the X-trigger target region during VR, but not at baseline or on-treatment, suggesting that X-trigger variants developed off treatment in JNJ-3989-treated patients. The presence of these variants did not impact off-treatment HBsAg kinetics.</div></div><div><h3>ClinicalTrial.gov Identifiers</h3><div>NCT03982186 and NCT0412954.</div></div><div><h3>Impact and implications</h3><div>Small-interfering RNA (siRNA) therapy with JNJ-3989 in patients with chronic hepatitis B induces potent, dose-dependent reductions in viral antigens, though the magnitude of decline varies among individuals. Baseline nucleotide polymorphisms in JNJ-3989 trigger target regions did not account for variability in HBsAg or HBeAg responses. Substitutions in siRNA trigger target regions were frequently detected during and after virologic relapse in JNJ-3989-treated patients, confirming antiviral target engagement. However, the emergence of these variants did not affect off-treatment HBsAg or HBV DNA kinetics. This study provides the first comprehensive clinical virology analysis of siRNA-based therapy in HBV infection, offering insight

AimsJNJ-73763989 （JNJ-3989）是一种小干扰RNA，由两个靶向HBsAg和HBx蛋白开放阅读框的触发器组成，旨在靶向所有HBV RNA降解。JNJ-3989 +核苷类似物（NA）治疗剂量依赖性降低慢性乙型肝炎（CHB）病毒抗原。在REEF-1 （NCT03982186）和REEF-2 （NCT0412954）研究中，在基线、治疗中以及停止所有治疗后病毒学复发（VR）患者中，评估了JNJ-3989 S-/ x触发靶区的病毒序列变化。方法从血浆样品中提取HBV DNA/RNA，采用新一代测序技术对HBV基因组进行测序。核苷酸变异被定义为与通用HBV参考序列的变化（读取频率>；15%）。结果：JNJ-3989靶区与S-/ x -触发器2-18位互补的基线多态性分别存在于10.1%和2.4%未接受治疗的患者中，对JNJ-3989诱导的HBsAg下降无相关影响。在jnj -3989治疗的病毒学抑制（VS） VR患者中，x触发靶区感兴趣位置（POI）的变异在治疗后更频繁地观察到（分别为55.8%和5.7%）。在JNJ-3989和na -对照治疗的VS合并VR患者中，分别有32.1%和19.4%的患者在治疗后观察到s触发POI的变异。在接受jnj -3989治疗的患者中，在VR期间S-/ x触发目标POI是否存在变异，治疗后HBsAg动力学没有差异。结论基线序列多态性不影响JNJ-3989治疗效果。jnj -3989治疗后经历VR治疗的患者在VR期间有x触发靶区变异，但在基线或治疗期间没有，这表明x触发变异在jnj -3989治疗后的患者中出现。这些变异的存在不影响治疗后的HBsAg动力学。影响和意义使用JNJ-3989治疗慢性乙型肝炎患者的小干扰RNA （siRNA）可诱导病毒抗原的有效剂量依赖性降低，尽管下降的幅度因人而异。JNJ-3989触发靶区的基线核苷酸多态性不能解释HBsAg或HBeAg反应的变异性。在jnj -3989治疗的患者病毒学复发期间和之后，经常检测到siRNA触发靶区域的替换，证实了抗病毒靶标的作用。然而，这些变异的出现并不影响治疗后的HBsAg或HBV DNA动力学。该研究首次对基于siRNA的HBV感染治疗进行了全面的临床病毒学分析，为抗病毒siRNA治疗的更广泛发展提供了相关见解。X-trigger replacement对于JNJ-3989或其他hbv靶向sirna的潜在再治疗的临床意义仍有待确定。

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引用次数: 0

HBV X protein regulates cancer stemness and tumor invasiveness through SENP1 in hepatocellular carcinoma 在肝细胞癌中，HBV X蛋白通过SENP1调控肿瘤的干性和肿瘤侵袭性

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2025-10-08 DOI: 10.1016/j.jhepr.2025.101620

Yu-Chih Wu , Yen-Chiao Huang , Yung-Che Kuo , Mai-Huong Thi Ngo , Kam-Fai Lee , Yen-Tseng Sung , Hsiao-Feng Wang , Shin-Lian Doong , Liang-Mou Kuo , Te-Sheng Chang , Yen-Hua Huang

Background & Aims

The niche in hepatocellular carcinoma (HCC) critically influences cancer stem cell (CSC)-associated properties, including stemness, early recurrence, and poor prognoses. HBV infection acts as a niche driver for tumor progression and malignancy. While the HBV X (HBx) protein has been linked to CSC-associated properties, the underlying molecular mechanisms remain unclear.

Methods

Paired tumor and peritumor tissues from 211 patients with HCC were analyzed to correlate SENP1, OCT4, SNAIL, PIN1, and TWIST expression with overall survival (OS) and disease-free survival (DFS) using a Kaplan-Meier survival analysis. Validation was performed using HCC microarray data (n = 167). HBx-SENP1’s role in regulating CSC-associated properties was examined in vitro (stemness expression, sphere formation, CD133⁺ cells, migration/invasion, and sorafenib sensitivity) and in vivo using an orthotopic xenograft model.

Results

Clinically, SENP1 expression was correlated with OCT4, SNAIL, and TWIST (p <0.001), and was associated with poor OS (69.2 vs. 172.8 months, p <0.001) and DFS (15.8 vs. 39.7 months, p <0.001). SENP1 expression was correlated with gene sets linked to HCC recurrence and embryonic stem cell signatures. In HBV-related HCC, elevated SENP1 (7.8 vs. 15.7 months, p = 0.003), OCT4 (7.8 vs. 16.7 months, p <0.001), SNAIL (8.6 vs. 15.7 months, p = 0.012), and TWIST (8.2 vs. 15.5 months, p = 0.028) were linked to early recurrence. Mechanistically, HBx induced CSC-associated properties through SENP1, including sphere formation, CD133⁺ cells, migration/invasion, and sorafenib resistance. SENP1-knockdown decreased HBx-induced pulmonary metastases and sorafenib refractoriness in vivo.

Conclusions

HBx-induced SENP1 is critical for CSC properties. SENP1 can serve as a novel biomarker for early recurrence, metastasis, and drug resistance, particularly in HBV-related HCC.

Impact and implications

Early recurrence, tumor metastasis, and drug resistance are significant therapeutic challenges in hepatocellular carcinoma (HCC), which are closely associated with cancer stem cell (CSC)-related properties. In this study, we demonstrated that HBx-induced SENP1 expression regulates CSC-related properties and tumor metastasis, particularly in HBV-related HCC, in clinical, in vitro, and in vivo settings. Findings from this research highlight that HBx-induced SENP1 is crucial for promoting CSC-associated properties in HCC. SENP1 could serve as a novel biomarker of early tumor recurrence and metastasis, especially for HBV-related HCC.

背景和目的肝细胞癌（HCC）的生态位严重影响癌症干细胞（CSC）相关特性，包括干细胞性、早期复发和预后不良。HBV感染是肿瘤进展和恶性肿瘤的利基驱动因素。虽然HBV X （HBx）蛋白与csc相关特性有关，但其潜在的分子机制尚不清楚。方法采用Kaplan-Meier生存分析方法，分析211例HCC患者的肿瘤和肿瘤周围组织中SENP1、OCT4、SNAIL、PIN1和TWIST的表达与总生存期（OS）和无病生存期（DFS）的相关性。使用HCC微阵列数据（n = 167）进行验证。HBx-SENP1在体外（干细胞表达，球体形成，CD133+细胞，迁移/侵袭和索拉非尼敏感性）和体内使用原位异种移植模型中调节csc相关特性的作用。结果临床中，SENP1表达与OCT4、SNAIL和TWIST相关（p <0.001），与不良OS （69.2 vs. 172.8个月，p <0.001）和DFS （15.8 vs. 39.7个月，p <0.001）相关。SENP1的表达与与HCC复发和胚胎干细胞特征相关的基因集相关。在hbv相关的HCC中，SENP1 （7.8 vs. 15.7个月，p = 0.003）、OCT4 （7.8 vs. 16.7个月，p <0.001）、SNAIL （8.6 vs. 15.7个月，p = 0.012）和TWIST （8.2 vs. 15.5个月，p = 0.028）升高与早期复发有关。在机制上，HBx通过SENP1诱导csc相关特性，包括球体形成、CD133+细胞、迁移/侵袭和索拉非尼耐药性。在体内，senp1敲低降低了hbx诱导的肺转移和索拉非尼的难治性。结论shbx诱导的SENP1对CSC的性质至关重要。SENP1可以作为早期复发、转移和耐药的新型生物标志物，特别是在hbv相关的HCC中。影响和启示早期复发、肿瘤转移和耐药是肝细胞癌（HCC）治疗的重大挑战，这些与癌症干细胞（CSC）相关的特性密切相关。在这项研究中，我们证明了在临床、体外和体内环境中，hbx诱导的SENP1表达调节csc相关特性和肿瘤转移，特别是在hbv相关的HCC中。本研究结果强调，hbx诱导的SENP1对于促进HCC中csc相关特性至关重要。SENP1可以作为早期肿瘤复发和转移的一种新的生物标志物，特别是对于hbv相关的HCC。

{"title":"HBV X protein regulates cancer stemness and tumor invasiveness through SENP1 in hepatocellular carcinoma","authors":"Yu-Chih Wu , Yen-Chiao Huang , Yung-Che Kuo , Mai-Huong Thi Ngo , Kam-Fai Lee , Yen-Tseng Sung , Hsiao-Feng Wang , Shin-Lian Doong , Liang-Mou Kuo , Te-Sheng Chang , Yen-Hua Huang","doi":"10.1016/j.jhepr.2025.101620","DOIUrl":"10.1016/j.jhepr.2025.101620","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The niche in hepatocellular carcinoma (HCC) critically influences cancer stem cell (CSC)-associated properties, including stemness, early recurrence, and poor prognoses. HBV infection acts as a niche driver for tumor progression and malignancy. While the HBV X (HBx) protein has been linked to CSC-associated properties, the underlying molecular mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>Paired tumor and peritumor tissues from 211 patients with HCC were analyzed to correlate <em>SENP1</em>, <em>OCT4</em>, <em>SNAIL</em>, <em>PIN1</em>, and <em>TWIST</em> expression with overall survival (OS) and disease-free survival (DFS) using a Kaplan-Meier survival analysis. Validation was performed using HCC microarray data (n = 167). HBx-SENP1’s role in regulating CSC-associated properties was examined <em>in vitro</em> (stemness expression, sphere formation, CD133<sup>+</sup> cells, migration/invasion, and sorafenib sensitivity) and <em>in vivo</em> using an orthotopic xenograft model.</div></div><div><h3>Results</h3><div>Clinically, SENP1 expression was correlated with OCT4, SNAIL, and TWIST (<em>p <</em>0.001), and was associated with poor OS (69.2 <em>vs.</em> 172.8 months, <em>p</em> <0.001) and DFS (15.8 <em>vs.</em> 39.7 months, <em>p <</em>0.001). SENP1 expression was correlated with gene sets linked to HCC recurrence and embryonic stem cell signatures. In HBV-related HCC, elevated SENP1 (7.8 <em>vs.</em> 15.7 months, <em>p</em> = 0.003), OCT4 (7.8 <em>vs.</em> 16.7 months, <em>p</em> <0.001), SNAIL (8.6 <em>vs.</em> 15.7 months, <em>p</em> = 0.012), and TWIST (8.2 <em>vs.</em> 15.5 months, <em>p</em> = 0.028) were linked to early recurrence. Mechanistically, HBx induced CSC-associated properties through SENP1, including sphere formation, CD133<sup>+</sup> cells, migration/invasion, and sorafenib resistance. SENP1-knockdown decreased HBx-induced pulmonary metastases and sorafenib refractoriness <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>HBx-induced SENP1 is critical for CSC properties. SENP1 can serve as a novel biomarker for early recurrence, metastasis, and drug resistance, particularly in HBV-related HCC.</div></div><div><h3>Impact and implications</h3><div>Early recurrence, tumor metastasis, and drug resistance are significant therapeutic challenges in hepatocellular carcinoma (HCC), which are closely associated with cancer stem cell (CSC)-related properties. In this study, we demonstrated that HBx-induced SENP1 expression regulates CSC-related properties and tumor metastasis, particularly in HBV-related HCC, in clinical, <em>in vitro</em>, and <em>in vivo</em> settings. Findings from this research highlight that HBx-induced SENP1 is crucial for promoting CSC-associated properties in HCC. SENP1 could serve as a novel biomarker of early tumor recurrence and metastasis, especially for HBV-related HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101620"},"PeriodicalIF":7.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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