Intercellular Communication in the Progression from Fibrosis to HCC by Ectosomal HK1-Induced TGF-β Secretion

Extracellular vesicles (EVs) play a crucial role in intercellular communication in the tumor microenvironment (TME). Although EVs released by hepatocellular carcinoma (HCC) cells promote the differentiation of hepatic stellate cells (HSCs) into cancer-associated fibroblasts to remodel the TME, whether HSC-derived EVs directly affect HCC progression remains elusive. Here, we demonstrated that in hepatic fibrosis, transforming growth factor-β (TGF-β) stimulates the palmitoylation and subsequent plasma membrane localization of hexokinase 1 (HK1) in HSCs, leading to ectosomal HK1 secretion. This ectosomal HK1 is hijacked by HCC cells, which not only promotes HCC proliferation by accelerating glycolysis but also enhances the N-glycosylation of pro-TGF-β to stimulate TGF-β secretion from HCC cells, thereby creating a feedforward loop to promote HCC progression. The nuclear receptor Nur77 transcriptionally activates expression of the depalmitoylase ABHD17B to attenuate ectosomal HK1 release. However, TGF-β-activated Akt represses the function of Nur77 by inducing Nur77 phosphorylation and degradation. We further identified a small-molecule compound, PDNPA, that binds Nur77 to disrupt Akt-mediated Nur77 degradation, thereby inhibiting HCC development. This study demonstrates an overlooked function of HK1 in promoting HCC development upon its release from HSCs and highlights PDNPA as a candidate for repressing HCC through the interception of ectosomal HK1 release.