Fenvalerate Induces Airway Epithelial Injury Through CHRM3-Associated NF-κB Activation

Abstract

Fenvalerate (FEN) is a widely used pyrethroid insecticide with potential respiratory toxicity; however, its contribution to chronic obstructive pulmonary disease (COPD)-related pathological processes remains unclear. We investigated molecular mechanisms linking FEN exposure to airway epithelial injury. COPD transcriptomic datasets were integrated with predicted FEN targets, and candidate genes were prioritized using machine-learning algorithms. Immune infiltration and single-cell transcriptomic analyses were used to examine immune associations and cell-type-specific expression. Molecular docking and molecular dynamics simulations assessed potential FEN-target interactions, followed by validation in BEAS-2B human bronchial epithelial cells. Intersecting FEN-COPD genes were enriched in inflammatory, immune-regulatory, neuroactive ligand-receptor, and epithelial injury-related pathways. Eight candidate genes showed distinct expression patterns across airway epithelial and immune cell populations. Computational analyses supported a potentially stable FEN-CHRM3 interaction. In BEAS-2B cells, FEN reduced viability, increased IL-6 and IL-8 secretion, promoted apoptosis, upregulated CHRM3, and enhanced IκBα and p65 phosphorylation. Pharmacological inhibition of CHRM3 or NF-κB partially attenuated these responses. Thus, FEN-induced epithelial inflammation and apoptosis may involve CHRM3-associated NF-κB activation, providing mechanistic insight into pesticide-related respiratory toxicity.