Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is an aggressive tumor with a poor prognosis and high cancer-related mortality [1]. HCC accounts for nearly 85–90 % of primary liver cancer cases, and advances in the diagnosis and treatment of HCC have reduced the 20 % mortality caused by HCC [2]. Treatment for HCC involves transplantation and surgical resection for early-stage HCC patients; however, more than 80 % of patients diagnosed with HCC are in the late stage; thus, effective treatment for HCC is still lacking [3]. Plantamajoside (PMS) is extracted from Plantago Asiatica, is a phenylpropanoid glycoside, and has multiple biological functions, including anti-inflammatory and antioxidant properties [4]. A recent study found that PMS reduces cancer growth and metastasis via inhibition of MMP expression [5]. MMPs contain multiple members that are characterized by zinc-dependent endoproteases, and regulate the degradation of extracellular matrix, thus regulating the cancer invasion and metastasis. However, the detailed mechanisms are not clear. CXCR4 is a G protein-coupled receptor localized on the cell membrane, and the binding of CXCR4 and CXCL12 plays an important role in the transduction of extracellular signals into cells. Aberrant CXCR4 expression has been discovered in many types of cancers [6]. A previous study showed that CXCR4 expression is critical for hematopoiesis and is mostly expressed on epithelial cells, leukocytes and endothelial cells. Elevated expression of CXCR4 has been found in various types of tumors, including colon, kidney and brain [7]. CXCR4 expression has been regarded as a marker of aggressive tumor behavior and is positively associated with tumor size, grade, recurrence, and poor survival [8]. Multiple studies have shown that overexpression of CXCR4 contributes to tumor metastasis in the breast, brain, colon, and liver [9]. LY2510924 is a selective antagonist of CXCR4 that inhibits the binding of CXCL12 and CXCR4. LY2510824 inhibited tumor growth in a dose-dependent manner, especially for tumors with high CXCR4 expression [10]. In an AML model, the researchers found that LY2510924 strongly inhibits the expression of CXCR4 in the cell membrane and thereby represses downstream chemotaxis and prosurvival signals in tumor cells, presenting an antitumor function [11]. NUCC-390 is a water-soluble small molecule, that recapitulates the pharmacological ability of CXCL12. Therefore, NUCC-390 promotes the function of CXCL12, and further promotes its binding with CXCR4 [12]. Thus, we used LY2510924 and NUCC-390 to construct a CXCR4 inhibition and activation model in tumor cells. This study stablished cell models of CXCR4 inhibition and overexpression in HepG2 cells and found that the metastasis ability was inhibited, while the apoptosis of cells was elevated with PMS combined with CXCR4 inhibition treatment. We found increased expression of pro-apoptosis proteins and decreased expression of pro-metastasis proteins. The PI3K pathway is a critical regulator in the process of tumor progression and regulates extracellular matrix proteins to facilitate the tumor growth [13]. PTEN is a well-known tumor suppressor that mainly targets phosphatidylinositol 3,4,5-trisphosphate (PIP3), a PI3K product. Phosphorylation of AKT promotes the migration and invasion of tumor cells, and PTEN dephosphorylates PIP3, which further inactivates PI3K [14], thereby regulating the progression of tumor cells. Furthermore, we observed that these effects are regulated by the PI3K/AKT/Mcl-1/PARP pathway. Thus, the present study aimed to explore the function of CXCR4 inhibition in promoting the therapeutic effect of PMS.