Hepatic stellate cells drive hypoxia-inducible factor (HIF)-dependent metabolic rewiring and proliferation in hepatocellular carcinoma cells

Co-culture with activated hepatic stellate cells increases proliferation of hepatocellular carcinoma cells by rewiring glucose metabolism toward higher glycolysis and de novo nucleotide synthesis.

• Why it matters: Most HCC arises in a cirrhotic tumor microenvironment enriched in activated HSC-derived fibroblasts, but how HSC–HCC interactions drive metabolism-linked proliferation is incompletely defined.
• What they did: In a Transwell co-culture model, isotope tracing metabolomics quantified metabolic rewiring, while transcriptomics and immunofluorescence assessed HIF signaling; H2O2 was tested as a candidate crosstalk signal.
• The result: HSCs upregulate hypoxia-inducible factor signaling in HCC cells, contributing to metabolic rewiring and proliferation, suggesting HIF-linked pathways and H2O2-mediated signaling as therapeutic targets.