A Conserved FABP5high Macrophage Subset Promotes Fibrosis and Carcinogenesis in Advanced Liver Disease

Background and Aims The relationship between chronic liver disease and liver cancer remains poorly understood, and treatment options for advanced liver disease remain limited. This study aims to elucidate the dynamic evolution of cellular and molecular alterations from normal liver to diseased liver. Methods Single‐cell RNA sequencing was performed to profile the dynamic cellular variations from normal liver to diseased liver. Bioinformatics analyses were employed to assess tumour heterogeneity and the evolution of tumour microenvironment. Molecular biology validations were performed to investigate the findings. Results Through single‐cell RNA sequencing, we constructed a human liver landscape consisting of more than 130 000 single cells, from normal, cirrhotic tissue, primary liver cancer and paired adjacent tissues. We profiled both inter‐ and intra‐tumour heterogeneity of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. A dual role of the pro‐fibrosis and pro‐carcinogenesis FABP5 high macrophage subset was shown to be conserved throughout the progression of liver fibrosis and carcinogenesis; markers, spatial localization, origin, and functional pathways associated with FABP5 high macrophages were identified through in vitro and in vivo validation. Metabolic reprogramming of these conserved FABP5 high macrophages is implicated in the formation of cirrhotic and cancerous niches. Additionally, we also identified a subset of RGCC+COL4A1+ endothelial cells enriched in HCC tissues, which might experience endothelial‐mesenchymal transition and orchestrate the proliferation and invasion of cancer cells via angiogenesis. Conclusions Our findings provide insights into the evolution from chronic liver disease to liver cancer. These insights will contribute to the development of novel cell subset‐based therapeutics based on immunotherapy and targeted therapy.