ArticleJournal of hepatocellular carcinoma2026
ScRNA-Seq Deciphers an Autocrine EFNA1-EPHA1 Loop That Reprograms the Microenvironment in Hepatocellular Carcinoma.
Article in Journal of hepatocellular carcinoma, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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10 authors.
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Abstract
Background: Hepatocytes demonstrate significant heterogeneity between normal liver tissue and hepatocellular carcinoma (HCC), with malignant hepatocytes playing a crucial role in remodeling the tumor microenvironment through specific ligand-receptor interactions. However, the mechanisms by which hepatocytes drive HCC progression at the single-cell level remain poorly understood. Methods: We analyzed single-cell RNA sequencing datasets (GSE174748 and GSE166635) from the GEO database using CellChat to decode intercellular communication networks, which specifically revealed enhanced EPHA signaling in HCC hepatocytes and identified EFNA1-EPHA1 as the most prominent ligand-receptor pair. This key finding was validated through immunofluorescence analysis in both clinical HCC tissues and HepG2/LO2 cell lines, and its clinical relevance was assessed using the TCGA-LIHC dataset via UALCAN. Results: Single-cell analysis revealed that HCC hepatocytes act as both senders and receivers of pro-tumorigenic signals, with upregulated expression of malignancy-related genes (AFP, ACSL4, and SERPINA1). CellChat inference demonstrated significantly strengthened outgoing interaction signals from hepatocytes in the HCC microenvironment. The EFNA1-EPHA1 axis was identified as a key mediator of hepatocyte-microenvironment crosstalk, showing marked activation in HCC tissues and high co-expression in HepG2 cells. TCGA analysis confirmed EFNA1 upregulation in HCC, correlating with advanced clinical stage, higher tumor grade, and metastatic events. Conclusion: Our study provides single-cell resolution evidence that malignant hepatocytes promote HCC progression through autocrine and paracrine signaling via the EFNA1-EPHA1 axis, reshaping the tumor microenvironment. These findings delineate a key autocrine-paracrine mechanism in HCC progression and nominate the EFNA1-EPHA1 axis as a promising candidate for therapeutic development.
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