We demonstrated that the lncRNA MIR181A1HG was progressively upregulated in tissues and serum EVs from healthy normal controls to CRC and paired liver metastatic groups. Additionally, we verified that HNRNPA2B1 mediated the packaging of MIR181A1HG into CRC cell-derived EVs, which in turn functioned as a ceRNA by sponging miR373-3p to activate HSCs via the TGFβRII/Smad2/3 signaling pathway. Furthermore, activated HSCs could secrete the chemokine CXCL12 to promote CRLM by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells in the liver, which resulted in liver metastasis.