Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
Université de Strasbourg, Strasbourg, France.
Nat Commun. 2021 Sep 17;12(1):5525. doi: 10.1038/s41467-021-25468-9.
Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2, CLEC5A, MARCO liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.
慢性肝脏疾病和肝细胞癌（HCC）是危及生命的疾病，治疗选择有限。缺乏临床相关/可行的实验模型阻碍了治疗方法的发现。在这里，我们开发了一种简单而强大的基于人肝细胞的系统，模拟了一种临床预后肝标志物（PLS），可预测长期肝脏疾病向 HCC 的进展。我们使用 PLS 作为读出值，然后在非酒精性脂肪性肝炎/纤维化/HCC 动物模型和患者来源的肝球体中进行验证，鉴定出一种组胺受体 H2（HRH2）阻断剂尼扎替丁，用于治疗晚期肝病和 HCC 化学预防。此外，通过对患者肝组织进行单细胞 RNA-Seq 分析的扰动研究，发现肝细胞和 HRH2、CLEC5A、MARCO 肝巨噬细胞是尼扎替丁的潜在靶点。PLS 模型结合患者组织的单细胞 RNA-Seq 可发现急需的靶点和治疗方法，用于治疗晚期肝病和预防癌症。
