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Histone modification reader proteins serve as key epigenetic regulators of anti-tumor immunity, yet their synergistic immune networks, combined prognostic roles and immune subtype heterogeneity remain poorly understood. Methods: Here, we integrated multi-omics data and graph attention networks (GAT) to systematically screen prognostic-associated histone reader genes. We then conducted analyses using the immunoassay pipeline and ultimately identified hub immune-related genes validated in independent external cohorts. Additional analyses, including single-cell RNA sequencing (scRNA-seq), molecular docking and multiple in silico functional assays, were performed based on retrospective public datasets. Results: Four core genes (CUL7, GPC1, NFYA, SLC25A5) exhibited robust prognostic performance and strong correlations with anti-tumor immunity. Both core and auxiliary genes participate in critical metabolic and immune pathways. Candidate drugs present differential binding affinity for their encoded proteins, with sapitinib designated as a promising agent. Conclusions: This work constructs an epigenetic immune regulatory network and a four-gene signature, offering promising biomarkers and actionable therapeutic targets for precision immunotherapy against CRC.<\/jats:p>","DOI":"10.3390\/genes17080848","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Graph-Based Multi-Omics Integration Reveals Prognostic Histone Modification Reader Genes and Candidate Drug Targets in Colorectal Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Xiangjun","family":"Cui","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"},{"name":"Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibo","family":"Xue","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijun","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Langlang","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyang","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"},{"name":"Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"},{"name":"Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"},{"name":"Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqiang","family":"Xing","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"},{"name":"Inner Mongolia Key Laboratory of Life Health and Bioinformatics, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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