Background: Apoptosis undergoes dynamic changes during tumor progression and treatment and has complex effects on tumor development. Apoptotic cell-derived extracellular vesicles (Apo-EVs) have recently been recognized as key mediators of intercellular communication, but their role in hepatocellular carcinoma (HCC) remains unclear.
Methods: We performed a series of in vitro and in vivo experiments to investigate the effects of tumor-derived Apo-EVs on HCC cell proliferation, apoptosis, and metabolic remodeling. Additional mechanistic studies were conducted to identify the functional cargo molecules carried by Apo-EVs and to determine their roles in ATP synthesis and metabolic regulation.
Results: Tumor-derived Apo-EVs suppressed HCC cell proliferation and increased apoptosis. Mechanistically, Apo-EVs promoted apoptotic cell death by shifting cellular metabolism from aerobic glycolysis to oxidative phosphorylation. Notably, transmembrane protein 70 (TMEM70), which is transported by Apo-EVs, was identified as a key mediator of this process. TMEM70 participated in ATP synthesis and contributed to metabolic reprogramming in HCC cells.
Conclusions: Our study reveals a potential mechanism by which tumor-derived Apo-EVs promote apoptosis and metabolic remodeling in HCC. Apo-EV-associated TMEM70 may contribute to this process through its involvement in mitochondrial metabolism. These findings suggest that Apo-EVs and selected cargo molecules may represent promising therapeutic targets for HCC.
Keywords: Apoptotic cell-derived extracellular vesicles; Glycolysis; Hepatocellular carcinoma; Mitochondrial metabolism; Oxidative phosphorylation; TMEM70.
© 2026. The Author(s).