A Unique Intercellular Feedforward Loop From HK1 to TGF‐β1 Promotes the Progression of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) typically emerges in a fibrotic premalignant liver milieu, and hepatic stellate cells (HSCs) represent the predominant cell subtype implicated in hepatic fibrosis. The crosstalk between HCC cells and HSCs has been demonstrated to affect HCC progression. Our prior research revealed that the activation of HSCs in hepatic fibrosis is accompanied with secretion of hexokinase 1 (HK1), an enzyme catalysing the initial step of glycolysis, through large extracellular vesicles (lEVs), which are selectively internalised by HCC cells to promote their glucose metabolism and tumour progression. In the present study, we found that the boosted glucose metabolism in HCC cells can reciprocally activate HSCs, thereby facilitating the formation of a pro-tumourigenic fibrotic microenvironment. Specifically, HSCs-transmitted lEV HK1 was identified as a key factor that markedly enhances the ability of HCC cells to activate HSCs. Mechanistically, HK1 accelerates the metabolic flux of hexosamine biosynthesis pathway, thereby promoting N-glycosylation of pro-transforming growth factor-β (TGF-β)1 and facilitating its secretion from HCC cells, which subsequently activates HSCs. This HCC cell-induced HSC activation is accompanied by increased secretion of lEV HK1 from HSCs, establishing a feedforward loop between HCC cells and HSCs. Furthermore, this intercellular communication was confirmed to exacerbate HCC progression in several mouse models, and disrupting this communication significantly inhibited HCC progression. Together, this study highlights that targeting the disruption of this feedforward loop may represent a promising and effective therapeutic strategy for HCC treatment.