Elucidating the molecular mechanisms of PFOS-induced obesity using network toxicology and molecular docking

Obesity has emerged as a global public health crisis, with its prevalence escalating at an alarming rate. While genetic and lifestyle factors are well-established contributors, emerging evidence implicates environmental exposures, particularly endocrine-disrupting chemicals (EDCs), in the pathogenesis of obesity. Among these, perfluorooctanesulfonic acid (PFOS), a persistent organic pollutant, has garnered significant attention due to its ubiquitous presence in the environment and bio-accumulative properties. This study employs network toxicology to investigate the molecular mechanisms underlying obesity associated with EDCs using PFOS exposure as a case study. Through an integrative analysis of the CHEMBL, STITCH, GeneCards, and OMIM databases, we identified 92 overlapping molecular targets associated with both PFOS exposure and obesity. Subsequent rigorous screening using the STRING platform and Cytoscape software revealed 10 core targets, including FASN, SCD, ACSL1, CD36, and FABP1. Functional enrichment analysis via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway assessments demonstrated that these core targets are predominantly involved in the PPAR signaling pathway, metabolic pathways, fatty acid metabolism, biosynthesis of unsaturated fatty acids, fat digestion and absorption, GABAergic synapse, and lysosomal activity. Molecular docking simulations performed with AutoDock software further validated stable binding interactions between PFOS and these key targets. By elucidating these mechanistic insights, our study offers a theoretical foundation for understanding the role of PFOS in obesity pathogenesis. These findings not only enhance our comprehension of the molecular underpinnings of EDC-induced obesity but also pave the way for the development of early intervention strategies, improved health risk assessments, and targeted therapeutic approaches.