Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.