Integrated network toxicology and experimental validation identify VCAM1 as a candidate molecular link between pyrethroid exposure and keloid.

Abstract

BACKGROUND: Keloids are fibroproliferative skin lesions characterized by excessive extracellular matrix deposition. The potential molecular links between pyrethroid exposure and keloid-associated alterations remain unclear. METHODS: We integrated network toxicology, machine learning, single-cell transcriptomics, virtual gene perturbation, molecular docking, molecular dynamics simulation, external transcriptomic validation, and qRT-PCR to investigate candidate molecular links between pyrethroid exposure and keloid. RESULTS: A total of 127 shared candidate targets between pyrethroid insecticides and keloid were identified, mainly enriched in MAPK, PI3K-Akt, and FoxO signaling pathways. Three machine-learning algorithms prioritized VCAM1 and FGFR1. In GSE145725, both genes showed significant differential expression and high dataset-level discriminatory performance. In the integrated external validation cohort generated from GSE90051 and GSE158395, VCAM1 remained significantly upregulated and showed good discriminatory performance (AUC = 0.869), whereas FGFR1 showed weaker external support (AUC = 0.677) without significant differential expression. Molecular docking and 100-ns molecular dynamics simulation supported the structural plausibility of selected pyrethroid-target interactions, particularly theta-cypermethrin with VCAM1. Single-cell analysis characterized the cell-type-specific distribution of candidate genes, while virtual gene perturbation suggested a putative VCAM1-SOCS3 regulatory relationship. qRT-PCR further showed that 20 μM cypermethrin exposure for 24 h significantly increased VCAM1 mRNA expression in KEL FIB cells. CONCLUSION: VCAM1 emerged as the most consistently supported candidate linking cypermethrin exposure with keloid-associated molecular alterations, while the predicted VCAM1-SOCS3 relationship requires further mechanistic validation.

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