AbstractBackgroundCell division cycle‐associated 8 (CDCA8) is involved in numerous signaling networks, and it serves a crucial modulatory function in multiple malignant tumors. However, its significance in prognosis and immune infiltration in hepatocellular carcinoma (HCC) remains unclear.Materials and methodsHerein, we examined the CDCA8 levels in tumor tissues, as well as its associated signaling pathways and correlation with immune infiltration. Additionally, we further clarified the prognostic significance of CDCA8 among HCC patients. HCC patient information was recruited from The Cancer Genome Atlas (TCGA). Using bioinformatics, the following parameters were analyzed among HCC patients: CDCA8 expression, enrichment analysis, immune infiltration, and prognosis analysis. Moreover, we employed in vitro investigations, such as, qRT‐PCR, immunohistochemistry (IHC), and cell functional experiments to validate our results.ResultsElevated CDCA8 expression in HCC patients was markedly associated with T stage, pathological status (PS), tumor status (TS), histologic grade (HG), and AFP. Elevated CDCA8 expression HCC patients exhibited reduced overall survival (OS) (p< 0.001), disease‐specific survival (DSS) (p< 0.001), and progress free interval (PFI) H(p< 0.001). According to the ROC analysis, the area under the curve (AUC) was 0.997. Multivariate analysis revealed that CDCA8 was a stand‐alone prognostic indicator of patient OS (p= 0.009) and DSS (p= 0.006). A nomogram was then generated based on the multivariate analysis, and the C‐indexes and calibration chart revealed excellent predictive performance in determining HCC patient outcome. Based on the GSEA analysis, CDCA8 modulated the P53, Notch, PPAR, E2F networks. We observed a direct link between CDCA8 levels and Th2 and T helper cells, and a negative link between CDCA8 levels and dendritic cells (DC), neutrophils, cytotoxic cells, and CD8 T cells. Furthermore, CDCA8 deficiency inhibited liver cancer cell proliferation and invasion.ConclusionIn conclusion, these findings indicate that CDCA8 is a new molecular bioindicator of HCC patient prognosis, and it is an excellent candidate for therapeutic target against HCC.