Introduction:　Kinesin　family　member　20A　(KIF20A)　is　essential　for　cell　proliferation　and　is　implicated　in　promoting　tumor　progression,　but　its　role　in　hepatocellular　carcinoma　(HCC)　remains　poorly　studied.　Methods:　Through　the　analysis　of　bulk　RNA-sequencing　(bulk　RNA-seq)　and　single-cell　RNA　sequencing　(scRNA-seq)　data,　the　expression　of　KIF20A　and　its　relationship　with　diagnosis,　prognosis,　and　the　immune　microenvironment　were　examined.　The　association　between　KIF20A　and　the　malignant　progression　and　metastasis　of　HCC　was　confirmed　through　in　vitro　and　in　vivo　experiments.　Furthermore,　patient　re-staging　was　performed　using　Recursive　Partitioning　Analysis　(RPA)　to　enhance　clinical　benefit.　Results:　In　this　study,　we　firstly　found　KIF20A　was　overexprerssed　in　HCC　both　by　bulk　RNA-seq　and　scRNA-seq,　and　then　the　overexpression　of　KIF20A　significantly　promoted　the　proliferation,　invasion,　and　metastasis　in　vitro.　In　vivo,　the　overexpression　of　KIF20A　promoted　the　growth　and　lung　metastasis　of　HCC.　Furthermore,　gene　set　variation　analysis　of　bulk　RNA-seq　and　scRNA-seq　revealed　that　KIF20A　might　be　associated　with　cell　cycle　related　signaling　pathways　of　E2F　and　G2M,　and　overexpression　of　KIF20A　inhibited　the　activity　of　p21　and　bax,　as　well　as　shortened　G2　phase.　Importantly,　we　found　that　KIF20A　could　induce　T　cell　exhaustion　via　the　SPP1-CD44　axe　using　scRNA-seq.　Additionally,　KIF20A　was　also　correlated　with　the　expression　of　immune　checkpoint　inhibitors　(ICIs),　and　KIF20Ahigh　subgroup　might　be　benefited　from　the　ICIs　therapy.　Conclusion:　KIF20A　emerges　as　a　pivotal　driver　of　HCC　progression,　intricately　regulating　cell　cycle　pathways　and　modulating　immune　responses,　which　position　KIF20A　as　a　promising　target　for　HCC　management.　Copyright　©　2024　Su,　Zhong,　He,　You,　Xin,　Wang　and　Liu.