Integrating network toxicology, machine learning, gut microbiome analysis, and structural validation to reveal the molecular mechanism linking PFOA and PFOS exposure to age-related macular degeneration

Purpose Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are two ubiquitous persistent organic pollutants. Currently, little is known about the potential mechanisms of PFOA and PFOS in ophthalmic diseases. This study systematically investigates the effects of PFOA and PFOS exposure on age-related macular degeneration (AMD), aiming to identify potential targets and elucidate associated molecular mechanisms. Methods Differential expression analysis across multiple transcriptomic datasets was performed to identify AMD-associated genes. Network toxicology, machine learning, Mendelian randomization, gut microbiota profiling, molecular docking, and MD simulations were subsequently integrated to characterize the interactions between PFOA/PFOS and their protein targets. Results We first performed toxicity prediction to identify 97 potential targets linking these toxins to AMD. Subsequently, integrating bioinformatics with 128 machine learning algorithms further identified four key core genes: SLC1A4, ADAM17, EGFR, and MAPK10. Potential regulatory mechanisms were mapped using TF-miRNA-mRNA networks and GeneMANIA. Mendelian randomization (MR) validated causal relationships between core genes SLC1A4 and ADAM17 and AMD. Molecular docking and kinetic simulations confirmed stable interactions between PFOA/PFOS and their targets. Our findings reveal the pivotal roles of inflammatory responses, oxidative stress, and amino acid metabolism disorders in the pathogenic mechanisms of these toxins. Analysis of the gutMGene gut microbiome database identified specific bacteria potentially acting through metabolites to influence human genes enriched in inflammatory signaling pathways, thereby promoting the toxic effects of PFOA/PFOS on AMD. This established a “toxin-gut bacteria-metabolite-gene” relationship network. Conclusion This study elucidates the underlying molecular mechanisms and signaling pathways linking PFOA/PFOS exposure to AMD, identifying SCL1A4 and ADAM17 as key targets for PFOA/PFOS-induced AMD. These findings not only provide new insights into the role of environmental pollutants in AMD pathogenesis but also offer an analytical framework for elucidating the effects of other environmental toxins on ocular diseases.