Background: Transarterial chemoembolization (TACE) combined with sorafenib is a common therapeutic strategy for hepatocellular carcinoma (HCC). However, sorafenib resistance (SFR) remains a major clinical obstacle. Evidence suggest that TACE reshapes the tumor microenvironment (TME), creating an external high-glucose (HG) and internal low-glucose (LG) niche. In this context, hyperglycemia-driven lysophosphatidic acid (LPA) production accelerates HCC progression. Moreover, intercellular communication via extracellular vesicles (EVs) has been linked to drug resistance. Despite these insights, the SFR mechanism by which HG-induced LPA regulates EV uptake and signaling is unclear. Methods: ELISA, immunohistochemistry, Western blot, CCK-8, Annexin V-7AAD, bioinformatics, and hyperglycemic models were performed to assess the HG-LPA-EV connection in cell, blood, and surgical samples. Nanoparticle characterization, confocal imaging, GST pull-down, dominant mutants, and UEA-1 blot were used to check Arf6 activation, CD147 fucosylation, and EV-stimulated signaling. Bilateral CDX models, GFP-CD63 imaging, and combinational treatments were performed to further elucidate the SFR mechanism. Results: SFR emerges in hyperglycemic HCC patients with elevated LPA levels. Mechanistically, HG-induced LPA elevation promotes the uptake of LG-derived EVs (LG-EVs), thereby driving resistance. LPA activates ADP-ribosylation factor 6 (Arf6), which enhances macropinocytosis-mediated LG-EV uptake. Further, LG conditions increase fucosyltransferase 1 (FUT1)-dependent CD147 fucosylation on EV surfaces. Uptake of CD147⁺ LG-EVs subsequently promotes SFR by activating the fucosylation-dependent AKT/mTOR/4EBP1 signaling pathway. Importantly, inhibition of LPA-Arf6-mediated EV macropinocytosis significantly improves the sorafenib efficacy. Conclusion: Our findings uncover a previously unrecognized mechanism mediated by differential TME and CD147⁺ EV macropinocytosis in HCC and highlight the LPA-Arf6-macropinocytosis as a novel targeting axis to overcome SFR in HCC.
Keywords: Extracellular vesicles; Hepatocellular carcinoma; Lysophosphatidic acid; Macropinocytosis; Sorafenib resistance.
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