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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. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo ; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl 4). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment. • LPS modification enhances the scavenging effect of Clodronate liposomes on macrophages. • LPS-modified Clodronate liposomes with small particle can actively target HSCs. • LPS-modified Clodronate liposomes with small particle significantly inhibited the liver fibrosis. [ABSTRACT FROM AUTHOR]