The crotonylation reader DPF2 promotes the development and progression of colon adenocarcinoma through...

The crotonylation reader DPF2 has been implicated in tumor progression, but its role in colon adenocarcinoma (COAD), especially in cell-type-specific immune regulation and metabolic reprogramming, remains unclear.

We conducted an integrative multi-omics study combining genetic association analysis for COAD, public transcriptomic validation data, CRC-context single-cell and spatial transcriptomic datasets used as supportive expression evidence, circulating metabolite profiling, and clinical immunohistochemistry. Two-sample Mendelian randomization was used to evaluate the association between genetically predicted expression of crotonylation-related genes and COAD risk, followed by validation and mechanistic analyses centered on DPF2.

Among 16 crotonylation-related candidate genes with available cis-eQTL evidence, only DPF2 showed a significant positive association with COAD risk. DPF2 was consistently upregulated in GEO datasets, TCGA-COAD, and clinical samples, and high DPF2 expression was associated with advanced disease and poor overall survival. Single-cell MR identified the strongest risk-associated signal in TCL1A⁺ FCER2⁺ B cells, with a suggestive association in CD8⁺ S100B⁺ T cells. Supportive analyses using public CRC-context single-cell and spatial transcriptomic datasets further indicated heterogeneous immune-cell expression and tumor-region enrichment of DPF2. In addition, DPF2 was significantly associated with 11 COAD-related circulating metabolites, and mediation analyses suggested partial mediation through Ximenoylcarnitine (C26:1), 16α-hydroxy DHEA 3-sulfate, and Andro steroid monosulfate C19H28O6S (1).

DPF2 is a crotonylation reader associated with COAD risk and progression. Its effects may involve cell-type-specific immune regulation and partial mediation through metabolic reprogramming. While the primary causal inference of this study focused on COAD, complementary single-cell and spatial transcriptomic findings from broader CRC datasets provided supportive expression-level evidence consistent with these associations.