ArticleMolecular diversity2026
PFOS exposure is linked to immune-metabolic disruption in MASLD: integrated population, computational, and experimental evidence.
Article in Molecular diversity, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying molecular mechanisms remain incompletely characterized. We constructed an integrated analytical framework combining population epidemiology, network toxicology, machine learning, transcriptomic analysis, single-cell mapping, molecular docking, and experimental validation. NHANES data (n = 1,834) were analyzed to assess the association between serum PFOS concentrations and FLI-defined MASLD. Machine-learning analyses using LASSO and SVM-RFE prioritized candidate genes from 874 overlapping PFOS-MASLD-associated genes. Single-cell RNA sequencing resolved cell-type-specific expression patterns, while molecular docking evaluated potential PFOS-protein interactions. A 12-week murine exposure model provided in vivo validation. Epidemiological analysis identified a nonlinear association between serum PFOS and MASLD odds (p < 0.001), with effects evident at background exposure levels (7.76 ng/mL). Convergent machine-learning analyses prioritized five candidate genes: CYP7A1, GRIA3, PHLDA1, SOCS2, and WNT5A. An exploratory five-gene model yielded an apparent AUC of 0.998 (95% CI 0.993-0.998) within the analyzed transcriptomic dataset. Single-cell analysis revealed cell-type specificity, with CYP7A1/PHLDA1 enriched in hepatocytes, SOCS2/WNT5A in hepatic stellate cells, and GRIA3 in T cells. Molecular docking predicted potential PFOS-protein interactions with the five candidate targets, with docking scores ranging from -6.3 to -9.3 kcal/mol. RT-qPCR analysis of PFOS-treated mouse liver showed transcriptional changes consistent with the computational predictions. PFOS-treated mice exhibited hepatic lipid accumulation, elevated liver injury markers, and lipid dysregulation. Together, these findings support an association between PFOS exposure and MASLD-related hepatic dysfunction and propose a hypothesis-generating immune-metabolic framework requiring prospective and direct mechanistic validation.
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