Exosomes, as important intercellular message transporters, can be secreted by hepatocellular carcinoma (HCC) cells and transported to adjacent cells, thus promoting their migration and invasion in turn. However, whether the exosomes secreted by HCC are affected by physical abnormalities, such as fluid shear stress (FSS), is still largely unknown. Here, we observed that 1.4 dyn/cm2 FSS could significantly increase the release of exosomes by up-regulating Rab27a and down-regulating Rab7 in HCC cells. Exosomes from FSS-induced HCC cells were more effective at encouraging recipient cell migration and invasion. Exosomes produced by static or FSS-stimulated cells were thoroughly analyzed using quantitative proteomics, and more than 1000 exosome proteins were found. Based on the differentially expressed proteins, IGF2, a potential migration-related protein, was discovered to be strongly expressed in FSS-stimulated cells, HCC tissues, as well as HCC patient-derived exosomes. Furthermore, we verified that exosomal IGF2 aggravated HCC migration and invasion via activating Ras/Raf/Erk signaling in recipient cells. Collectively, our data demonstrated that exosomes from FSS-stimulated HCC cells promote recipient cell migration through IGF2-Ras/Raf/Erk signaling, which might serve as potential targets for both cancer treatment and cancer prevention.AJCR Copyright © 2025.