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In this study, we identified zinc finger protein 282 (ZNF282), located on chromosome 7q, as a novel gene that contributes to CRC progression through comprehensive expression profiling using data from The Cancer Genome Atlas (TCGA) and single\u2010cell RNA sequencing combined with spatial transcriptomics in clinical CRC datasets. ZNF282 was overexpressed in tumor cells. High ZNF282 mRNA expression was associated with distant metastasis and served as an independent poor prognostic factor in CRC. In\u00a0vitro and in\u00a0vivo experiments using CRISPR\/Cas9\u2010mediated ZNF282 knockout CRC cell lines demonstrated significantly reduced tumor growth and cell proliferation, which were reversed by reexpression of ZNF282. Mechanistically, ZNF282 knockout impaired the G1\/S cell cycle transition and downregulated E2F1 and its downstream targets, CCNE1 and CCND1. These findings were supported by single\u2010cell RNA sequencing analysis, which showed ZNF282 enrichment in malignant epithelial cells linked to cell cycle pathways. Motif scanning further identified a putative ZNF282 binding site upstream of the E2F1 transcription start site, suggesting that ZNF282 may enhance E2F1 expression by facilitating the activity of an upstream regulatory region. In conclusion, ZNF282 is a novel gene that promotes CRC progression in part by enhancing cell cycle progression possibly via E2F1 activation. 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