Genomic and transcriptomic insights into aflatoxin-induced intrahepatic cholangiocarcinoma: an integrated pathway and...

Environmental and chemical exposures are major yet incompletely characterized drivers of human carcinogenesis. Aflatoxin, a potent food-borne mycotoxin, has been implicated in tumor initiation, proliferation, and immune suppression in intrahepatic cholangiocarcinoma (ICC), but its genomic mechanisms remain poorly defined.

We employed extensive literature data mining (LDM) to identify genes associated with both aflatoxin exposure and ICC, enabling construction of a mechanistic genetic pathway linking exposure to disease. These pathways were further evaluated using a meta-analysis of five Gene Expression Omnibus (GEO) expression datasets, followed by functional annotation to characterize their biological roles.

LDM identified 1,754 ICC-associated genes, of which 427 were also linked to aflatoxin, with 154 positioned as potential intermediate regulators connecting aflatoxin exposure to ICC. Meta-analysis revealed significant expression alterations in six genes upon aflatoxin exposure, including upregulation of CRP, CDK2, AXL, and MIR221 (overexpression >50%, p < 0.05) and downregulation of F2 and BUB1B (reduced expression >60%, p < 0.014). Co-expression analysis indicated strong interactions among these regulators (Fisher's Z > 0.53, p < 0.05), suggesting coordinated molecular responses associated with ICC progression. Functional annotation further highlighted inflammatory responses, cytokine dysregulation, and kinase-related signaling as key processes potentially linking aflatoxin exposure to ICC development.

These findings provide a systems-level view of the genomic mechanisms underlying aflatoxin-associated ICC carcinogenesis and identify candidate molecular mediators linking environmental toxin exposure to tumor development. This integrative framework may facilitate exposure-informed biomarker discovery and potential preventive or therapeutic strategies, particularly in regions where aflatoxin exposure remains prevalent.