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Graphical abstract Schematic illustration of the miR-4521-FAM129A axis in HCC malignancy. FAM129A negatively correlates with miR-4521, leading to suppressed migration and invasion by the TIMP-1/MMP9/MMP2 and EMT pathways. miR-4521-FAM129A axial regulation reduces proliferation and induced apoptosis via the p-FAK/p-AKT/MDM2/P53 and p-FAK/p-AKT /BCL-2/BAX/Cytochrome-C/Caspase-3/Caspase-9 pathways, respectively., Highlights • MiR-4521 deficiency reversely correlates with FAM129A upregulation in HCC. • MiR-4521 suppresses the in vitro migration and invasion capacities of HCC cells. • FAM129A is a direct and efficient target of miR-4521 in HCC cell invasiveness. • MiR-4521-FAM129A axis regulates HCC progression and metastasis via TIMP-1/MMP2/MMP9 and p-FAK/p-AKT pathway., Introduction Globally, hepatocellular carcinoma (HCC) is the sixth most common malignancy and it has the fourth highest mortality. MicroRNAs play a significant part in biological processes in cell formation and advancement by targeting genes in many cancers including HCC. Objective In the present study we examine the involvement of miR-4521 and FAM129A correlations in HCC occurrence and progression. Methods Expression levels of miR-4521 and FAM129A in HCC tissues and cells were detected. Immunohistochemistry was carried out to detect expression of FAM129A, MMP9 and TIMP-1 in HCC tissues. Western blot assays were used to examine expression levels of different genes involve in signaling pathways. Transwell chamber, MTT and wound healing assays were performed to check cell migration, invasion and proliferation rates. Results Overexpression of FAM129A positively correlated with upregulation of MMP9 and negatively correlated with TIMP-1 in HCC patient samples, which encouraged progression and metastasis of HCC. An antagonistic relation between miR-4521 and FAM129A was detected in current study, down-regulation of miR-4521 and up-regulation of FAM129A was demonstrated in HCC tissues and cell lines as compare to normal tissue samples and the normal cell line LO2. Overexpressing miR-4521 and silencing FAM129A impaired HCC cell migratory and invasive properties and suppressed cell proliferation. Mutually, miR-4521-FAM129A axial regulation inhibited in vitro proliferation of cells by promoting apoptosis through the p-FAK/p-AKT/MDM2/P53 and p-FAK/p-AKT/BCL-2/BAX/Cytochrome-C/Caspase-3/Caspase-9 pathways, respectively, and suppressed the migration and invasion capabilities of HCCLM3 and HepG2 cells via the TIMP-1/MMP9/MMP2 and p-FAK/p-AKT pathway. Conclusion Our work found the axial regulation mechanism of miR-4521-FAM129A in HCC. Deficiency of miR-4521 and abundance of FAM129A synergistically enhanced cancer progression by increasing cell proliferation and malignant invasion and by inhibiting apoptosis. These discoveries suggest that miR-4521/FAM129A might play a vital role in hepatic cancer progression and could be a candidate for its therapy.