| Summary: | Liver zonation is fundamental to normal liver function, and numerous studies have investigated the microstructure of normal liver lobules. However, only a few studies have explored the zonation signature in hepatocellular carcinoma (HCC). In this study, we investigated the significance of liver zonation in HCC with the help of single-cell RNA sequencing (scRNA-seq) and multicolor immunofluorescence staining. Liver zonation-related genes were extracted from the literature, and a three-gene model was established for HCC prognosis. The model reliability was validated using bulk RNA and single-cell RNA-level data, and the underlying biological mechanism was revealed by a functional enrichment analysis. The results showed that the signaling pathways of high-risk groups were similar to those of perivenous zones in the normal liver, indicating the possible regulating role of hypoxia in HCC zonation. Furthermore, the co-staining results showed that the low-grade tumors lost their zonation features whereas the high-grade tumors lost the expression of zonation-related genes, which supported the results obtained from the sequencing data.
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