肝源性祖细胞 (HPCs) 在炎症微环境中的恶性转化是肝癌发生的根本原因，然而潜在的分子机制仍然不清楚。通过单细胞RNA测序 (scRNA) 鉴定了HPCs亚群，并调查了原发性HCC模型中HPCs的表型。此外，还对HPCs衍生的器官样体进行了批量RNA测序 (RNA-seq) 和蛋白质组分析。研究发现，在HCC模型中，肿瘤从周围组织中的HPCs开始形成，在第16周。而且，通过NF-κB信号转导，巨噬细胞来源的TWEAK/Fn14促进了HPCs中抑制分化-1 (ID1)的表达，并且高水平的ID1导致了HPCs的异常分化。 机制上，ID1通过抑制HNF4α和Rap1GAP的转录来抑制HPCs的分化并促进增殖。最后，HCC患者的scRNA测序和临床标本的研究也证实，ID1的表达与HPCs的异常分化为癌干细胞有关，ID1水平高的患者预后较差。本研究为HCC的临床诊断和治疗提供了重要的干预靶点和理论基础。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.