Chain-length-specific immune transcriptomic signatures linking per- and polyfluoroalkyl substances to systemic lupus erythematosus

Immune dysregulation is central to systemic lupus erythematosus (SLE). However, the transcriptomic signatures linking per- and polyfluoroalkyl substances (PFAS) to SLE remain unclear. Peripheral blood mononuclear cell transcriptomic data from GSE81622 were integrated with SLE-associated genes and curated PFAS–gene interactions. Long-chain PFAS (PFOA, PFOS, and PFHxS) and short-chain PFAS (PFBA, PFBS, PFHxA, and GenX) were analysed separately. The workflow comprised differential expression analysis, network analysis, functional enrichment, immune deconvolution, machine learning, SHAP interpretation, molecular docking, and external validation in GSE50772. Of the 746 differentially expressed genes identified in SLE, 95 overlapped with long-chain PFAS targets and 19 with short-chain targets. MMP9, MX1, and CCL5 were prioritised for the long-chain group, whereas CCR3, ITGAL, and ATM for the short-chain group. Long-chain candidates mapped predominantly to interferon, antiviral, and extracellular matrix programmes, whereas short-chain candidates mapped to chemokine signalling, leukocyte adhesion, and DNA damage responses. In the internal test set, the LASSO models yielded AUROCs of 0.952 for the long-chain group and 1.000 for the short-chain group. In GSE50772, MMP9 and MX1 expression levels were higher in SLE, whereas CCR3, ITGAL, and ATM exhibited moderate expression; the CCL5 finding was not replicated. These findings identify chain-specific immune transcriptomic signatures and support a putative adverse outcome pathway. The proposed pathway links PFAS toxicokinetics to immune signalling, leukocyte dysregulation, and an SLE-related adverse outcome. However, the transcriptomic cohorts lacked individual-level PFAS measurements, and molecular docking assessed only structural feasibility. The framework therefore remains hypothesis-generating and does not establish that PFAS exposure causes SLE.