BACKGROUND: This study investigates the underlying mechanism of circKIAA1429 (hsa_circ_0084922) in hepatocellular carcinoma (HCC) progression. METHODS: circKIAA1429, SETD1A, NAP1L3, and GLIS2 expressions in HCC cells were detected by RT-qPCR or western blot. The stability of circKIAA1429 was tested after treatment with actinomycin D and Rnase R enzyme. circKIAA1429 expression was knocked down, followed by detection of cell proliferation, apoptosis, and migration/invasion using CCK-8, flow cytometry, and transwell. RIP and RNA pull-down were performed to validate the binding between circKIAA1429 and SETD1A, while ChIP analysis determined the enrichment of SETD1A and H3K4me3 or H3K27me3 on GLIS2 or NAP1L3 promoter. A nude mouse xenograft tumor model was establish to test the effect of circKIAA1429 on tumorigenicity. RESULTS: circKIAA1429 and NAP1L3 were highly expressed in HCC cells, while GLIS2 was poorly expressed. Knockdown of circKIAA1429 repressed cell proliferation/invasion/migration and facilitated apoptosis. Mechanistically, circKIAA1429 directly interacted with SETD1A to reduce the enrichment of SETD1A and H3K4me3 or H3K27me3 on GLIS2 or NAP1L3 promoter, thus diminishing GLIS2 expression and elevating NAP1L3 expression. In vivo, circKIAA1429 promotes tumorigenesis via GLIS2/NAP1L3. CONCLUSION: circKIAA1429 interacts with SETD1A to inhibit the enrichment of H3K4me3 and H3K27me3 on GLIS2 or NAP1L3 promoter, thus inhibiting/promoting the expression of GLIS2/NAP1L3 and accelerating the progression of HCC.