Multi-omics analysis of perfluorooctanoic acid and glioblastoma: insights from Mendelian randomization, network toxicology, and molecular docking.

Glioblastoma (GBM) is the most lethal primary brain tumor with limited treatment options. Perfluorooctanoic acid (PFOA), a ubiquitous "forever chemical" classified as a group 1 carcinogen by the IARC, can cross the blood-brain barrier and accumulate in neural tissue. This study aimed to determine the causal relationship between genetically predicted higher circulating PFOA levels and GBM risk, elucidate underlying molecular mechanisms, and identify potential therapeutic targets using an integrated multi-omics framework. Two-sample Mendelian randomization (MR) analysis was conducted using 23 single-nucleotide polymorphisms as instrumental variables. The outcome data were derived from the FinnGen consortium (endpoint C3_GBM, defined by ICD-O-3 morphology code 9440/3 with topography C71), with statistical analysis performed using SAIGE with saddlepoint approximation to address case-control imbalance. Network toxicology was applied to identify shared targets between PFOA and GBM, followed by protein-protein interaction network analysis and hub gene screening. The significance of gene set overlap was assessed using hypergeometric testing. Gene Ontology and KEGG enrichment analyses were performed on the full set of 86 overlapping genes to clarify biological pathways. Molecular docking assessed potential binding interactions between PFOA and hub proteins, and drug-target interaction analysis was conducted using the DGIdb database. MR analysis demonstrated a significant causal association between genetically predicted higher circulating PFOA levels and increased GBM risk (IVW OR = 2.64, 95% CI 1.13-6.20, p = 0.017), with no evidence of pleiotropy or heterogeneity. Network toxicology identified 86 overlapping targets (hypergeometric test p = 2.31 × 10⁻1⁸, OR = 3.12) and 9 hub genes (IL1B, MYC, BCL2, ALB, EGFR, ESR1, IL6, TNF, CASP3). Enrichment analyses of all 86 overlapping genes highlighted the AGE-RAGE signaling pathway, response to xenobiotic stimulus, chemical carcinogenesis-receptor activation, and positive regulation of glial cell proliferation. Molecular docking predicted potential PFOA binding to all hub proteins (binding energy < - 6.0 kcal/mol), with strongest affinities for MYC and TNF. Cisplatin emerged as the top drug repositioning candidate. This study provides the first genetic evidence supporting genetically predicted higher circulating PFOA levels as a causal risk factor for glioblastoma, potentially mediated by AGE-RAGE-driven neuroinflammation and oncogenic pathway activation, highlighting both environmental risk implications and therapeutic opportunities.