肝纤维化是肝细胞癌和肝病相关死亡的主要驱动因素。目前还没有获得批准的抗纤维化疗法，而且正在开发的化合物疗效有限。 TGF-β 信号传导增强可驱动肝星状细胞 (HSC)/肌成纤维细胞沉积胶原蛋白。在这里，我们的目的是剖析生物钟（CC）在控制 TGF-β 信号传导和肝纤维化中的作用。使用 CC 突变小鼠，从处于不同 CC 阶段和丧失的健康小鼠和纤维化小鼠中获得富集的 HSC 和肌成纤维细胞。 -在人类肝细胞和肌成纤维细胞的功能研究中，我们研究了 CC 和 TGF-β 信号传导之间的关系。我们通过单核转录组的生物信息学分析和基于细胞的模型验证来探索肝细胞-肌成纤维细胞的通讯。使用来自肝病患者的 MASH 纤维化和球状体小鼠模型，我们进行了概念验证研究，以验证药理学靶向性和临床可转化性。我们发现 CC 振荡器暂时门控 TGF-β 信号传导，并且这种调节在纤维化中被破坏。我们证明 HSC 和肌成纤维细胞含有功能性 CC，其有节奏地表达许多基因，包括纤维形成基因。肝细胞和肌成纤维细胞的扰动研究揭示了 TGF-β 激活和 CC 扰动之间的相互关系，这在患者来源的离体和体内模型中得到了证实。 CC-TGF-β 信号传导的药理学调节可抑制体内小鼠模型以及患者来源的肝球体的纤维化。CC 调节 TGF-β 信号传导，这种控制的破坏与患者的肝纤维化有关。不同模型的药理学概念验证研究表明，CC 是肝纤维化的候选治疗靶点，肝纤维化是全球未满足的医疗需求不断增长的一个方面。代谢性疾病引起的肝纤维化是一个全球健康挑战。许多肝脏功能全天都有节律，受生物钟 (CC) 控制。在这里，我们证明了 CC 的调节在慢性肝损伤时受到干扰，并且这种干扰会导致纤维化疾病。通过证明靶向 CC 的化合物可以改善患者衍生模型中的肝纤维化，这项研究为治疗患者纤维化提供了一种新的候选治疗策略。临床转化还需要更多研究。由于这些发现揭示了以前未被发现的促纤维化机制和治疗靶点，因此研究肝病的科学家、临床肝病学家和药物开发商对这项研究感兴趣。版权所有 © 2024 欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。

Liver fibrosis is the major driver for hepatocellular carcinoma and liver disease related death. Approved anti-fibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-β signaling drives collagen deposition by hepatic stellate cells (HSC)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-β signaling and liver fibrosis.Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC-phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-β signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and validation in cell-based models. Using mouse models for MASH fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability.We discovered that the CC-oscillator temporally gates TGF-β signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-β-activation and CC perturbation, which was confirmed in patient-derived ex vivo and in vivo models. Pharmacological modulation of CC-TGF-β signaling inhibited fibrosis in mouse models in vivo as well as patient-derived liver spheroids.The CC regulates TGF-β signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models uncover the CC as a therapeutic candidate target for liver fibrosis - a rising global unmet medical need.Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day being controlled by the circadian clock (CC). Here we demonstrate that the regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncovers a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.