Section snippets

Targeting the liver clock improves fibrosis by restoration of TGF-β signalling

The circadian clock (CC) regulates several functions in the liver and perturbations have been shown to be associated with liver disease. Crouchet, Dachraoui and coworkers studied the functional role of CC as a driver and therapeutic target in liver fibrosis. The authors show that CC oscillators are present in both hepatocytes and stellate cells, with the hepatocyte CC influencing stellate cell gene expression. They also demonstrated that the CC oscillator modulates the expression of TGF-β

A new mouse model resembling cholangiocellular carcinoma development in chronic cholangiopathies

Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma (CCA), which is difficult to diagnose and is associated with a high mortality rate. Huang, Wei and coworkers aimed to develop a mouse model of PSC-associated CCA using Mdr2^-/- mice, which exhibit a PSC-like cholestatic injury pattern, and injected them with proto-oncogenes AKT and Yap to induce tumour formation. They found that hydrodynamic tail vein injection of these genes led to robust tumour growth,

Induction of steatosis in primary human hepatocytes recapitulates key pathophysiological aspects of MASLD

Efficacy in animal models of metabolic dysfunction-associated steatotic liver disease (MASLD) often fails to translate into efficacy in humans, thereby requiring adjunctive systems to bridge this divide. In this issue, Kwon and coworkers demonstrate the utility of a cryopreserved primary human hepatocyte model in testing putative therapies. Their model recapitulated aspects of human MASLD in response to incubation with free fatty acids, which were corrected by firsocostat. These data provide

Long-term outcomes after HOPE in a real-world setting (HOPE-REAL study)

Preservation by liver machine perfusion is increasingly being implemented in clinical practice and helps overcome organ shortages by increasing utilisation of high-risk livers that need optimisation and assessment before transplantation. However, data on long-term outcomes are scarce. In this issue, Eden and coworkers report on recipient outcomes after liver transplantation (LT) with hypothermic oxygenated machine perfusion (HOPE) at 22 European LT centres between 2012 and 2021 (the HOPE-REAL

Patient-reported outcomes in chronic hepatitis delta: an exploratory analysis of the phase III MYR301 trial of bulevirtide

The study by Buti and coworkers investigated patient-reported outcomes (PROs) in the bulevirtide 301 registration trial for hepatitis D. Bulevirtide is a novel drug which blocks entry of HBsAg into hepatocytes and was fully approved by the EMA for the treatment of hepatitis D in 2023. The primary outcome of that pivotal study was published in the NEJM. However, it was unclear to what extent PROs also improve with this treatment. About half of the patients had cirrhosis and most had significant

Porto-sinusoidal vascular liver disorder with portal hypertension: natural history and long-term outcomes

The natural history of patients with portal hypertension due to porto-sinusoidal vascular disorder (PSVD) has not been fully described. In this month’s issue, Magaz, Giudicelli-Lett and coworkers present the results of a retrospective study in 587 patients from a multicentre cohort of patients with PSVD, of whom 64% were compensated at inclusion. Over a 5-year follow-up, 15% had first-time bleeding, and 18% experienced rebleeding. The 5-year cumulative incidence of new or worsening ascites was

Impact of pre-transplant ICI use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis

ICIs have revolutionised the treatment landscape of hepatocellular carcinoma (HCC), but the impact of pre-transplant ICI on allograft rejection, HCC recurrence, and overall survival is not known. Rezaee-Zavareh and coworkers report the results of a systematic review and individual patient data meta-analysis of 30 studies including 91 patients. Over a follow-up of 690.0 days, 24 patients had allograft rejections, 9 had HCC recurrences, and 9 died. Median time to rejection was 10.0 days, and

Philip Newsome∗ at Roger Williams Institute of Liver Studies and King’s Health Partner’s Centre for Translational Medicine, King’s College London, London, United Kingdom.

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靶向肝脏时钟通过恢复 TGF β信号传导来改善纤维化

生物钟 （CC） 调节肝脏中的多种功能，扰动已被证明与肝病有关。Crouchet、Dachraoui 及其同事研究了 CC 作为肝纤维化驱动因素和治疗靶点的功能作用。作者表明，CC 振荡器存在于肝细胞和星状细胞中，肝细胞 CC 影响星状细胞基因表达。他们还证明 CC 振荡器调节 TGF-β 的表达

一种类似于慢性胆管病中胆管细胞癌发展的新型小鼠模型

原发性硬化性胆管炎 （PSC） 与胆管癌 （CCA） 的高风险相关，胆管癌 （CCA） 难以诊断且死亡率高。Huang、Wei 及其同事旨在使用 Mdr2 ^-/- 小鼠开发 PSC 相关 CCA 的小鼠模型，这些小鼠表现出 PSC 样胆汁淤积损伤模式，并向它们注射原癌基因 AKT 和 Yap 以诱导肿瘤形成。他们发现，这些基因的流体动力学尾静脉注射导致肿瘤稳健生长，

原代人肝细胞脂肪变性的诱导概括了 MASLD 的关键病理生理学方面

代谢功能障碍相关脂肪性肝病 （MASLD） 动物模型中的疗效通常无法转化为人类的疗效，因此需要辅助系统来弥合这一鸿沟。在本期中，Kwon 及其同事展示了冷冻保存的原代人肝细胞模型在测试假定疗法中的实用性。他们的模型概括了人类 MASLD 响应与游离脂肪酸孵育的各个方面，这些方面由 firsocostat 校正。这些数据提供

在现实世界环境中 HOPE 后的长期结果（HOPE-REAL 研究）

通过肝脏机器灌注进行保存正越来越多地在临床实践中实施，并通过增加移植前需要优化和评估的高危肝脏的利用来帮助克服器官短缺。然而，关于长期结果的数据很少。在本期中，Eden 及其同事报告了 2012 年至 2021 年间在 22 个欧洲 LT 中心进行低温氧合机器灌注 （HOPE） 后接受者的结果（HOPE-REAL

慢性肝炎 delta 患者报告的结果：布列韦肽 III 期 MYR301 试验的探索性分析

Buti 及其同事的研究调查了丁型肝炎布列韦肽 301 注册试验中的患者报告结果 （PRO），布列韦肽是一种阻止 HBsAg 进入肝细胞的新型药物，并于 2023 年被 EMA 完全批准用于治疗丁型肝炎。该关键研究的主要结果发表在 NEJM 上。然而，目前尚不清楚这种治疗在 PRO 方面也有多大程度的改善。大约一半的患者患有肝硬化，大多数患者有明显的

门脉窦血管性肝病伴门静脉高压症：自然病程和远期结局

门窦血管疾病 （PSVD） 所致门静脉高压症患者的自然病程尚未得到充分描述。在本月的期刊中，Magaz、Giudicelli-Lett 及其同事介绍了一项回顾性研究的结果，该研究对来自 PSVD 患者多中心队列的 587 名患者进行研究，其中 64% 的患者在入组时得到了补偿。在 5 年的随访中，15% 的患者首次出血，18% 的患者再出血。新发腹水或恶化腹水的 5 年累积发生率

移植前 ICI 使用对 HCC 移植后结果的影响：系统评价和个体患者数据荟萃分析

ICI 彻底改变了肝细胞癌 （HCC） 的治疗格局，但移植前 ICI 对同种异体移植物排斥反应、HCC 复发和总生存期的影响尚不清楚。Rezaee-Zavareh 及其同事报告了 30 项研究（包括 91 名患者）的系统评价和个体患者数据荟萃分析的结果。在 690.0 天的随访中，24 例患者出现同种异体移植物排斥反应，9 例 HCC 复发，9 例死亡。拒绝的中位时间为 10.0 天，并且

Philip Newsome∗英国伦敦国王学院罗杰威廉姆斯肝脏研究所和国王健康合作伙伴转化医学中心。