Graph-Based Multi-Omics Integration Reveals Prognostic Histone Modification Reader Genes and Candidate Drug Targets in Colorectal Cancer.

Colorectal cancer (CRC) is driven by genetic alterations, epigenetic dysregulation and tumor microenvironment remodeling. 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. 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. 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. 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.