Multidimensional bioinformatics analysis reveals the potential carcinogenic role of acrylamide in colorectal cancer

This study aims to elucidate the molecular mechanisms underlying acrylamide-induced colorectal cancer (CRC), identify key carcinogenic genes, and investigate their roles in the immune microenvironment and gut microbiota, providing a theoretical foundation for early CRC diagnosis and prevention.

Acrylamide- and CRC-associated genes were screened from the GEO and CTDbase databases, and a Venn diagram was used to identify the intersection between acrylamide target genes and CRC differentially expressed genes (DEGs). Bidirectional two-sample Mendelian randomization (MR) analysis was employed to validate the causal relationship between these genes and CRC, followed by expression validation using TCGA data. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to elucidate gene functions, while clinical feature correlation analysis and single-sample gene set enrichment analysis (ssGSEA) were utilized to assess immune infiltration characteristics. Single-cell RNA sequencing (scRNA-seq) was conducted to determine the cell-type-specific expression of the identified genes. Additionally, MR-based mediation analysis was performed to explore the mediating effects of gut microbiota and immune cells, and molecular docking was used to simulate interactions between acrylamide and its target proteins.

Four key acrylamide-associated CRC driver genes (PAA-CDG) were identified: SF3B3, CSE1L, CD52, and TMEM158. Among them, SF3B3 (OR = 1.394) and CSE1L (OR = 1.188) were found to significantly increase CRC risk, potentially through activation of the PI3K-AKT pathway and induction of an immunosuppressive microenvironment. Conversely, CD52 (OR = 0.85) exhibited a protective role, likely by enhancing B cell-mediated anti-tumor immunity. Enrichment analysis revealed that these genes were primarily involved in extracellular matrix (ECM) remodeling, immune regulation, and PI3K-AKT signaling. Clinical correlation analysis further highlighted the association of PAA-CDG with age, body weight, and racial background. scRNA-seq analysis demonstrated that SF3B3 was highly expressed in proliferative T cells, whereas CD52 was enriched in B cells. MR-based mediation analysis indicated that Klebsiella abundance (mediating effect = 14 %) and CD4 + T cell subsets (17 %) partially mediated the association between these genes and CRC. Molecular docking confirmed strong binding affinities between acrylamide and SF3B3 (ΔG = -4.54 kcal/mol) and CSE1L (ΔG = -5.59 kcal/mol), suggesting potential interference with splicing complex assembly and nuclear transport mechanisms.

Acrylamide may drive CRC progression through dysregulated signaling and immune modulation. Validation across cohorts and experimental models is needed to confirm key targets and inform precision prevention. These findings highlight acrylamide's public health relevance and support regulatory efforts to limit exposure from dietary and environmental sources.