Environmentally Relevant Microplastic Inhalation Drives Pulmonary Fibrosis via a FABP5–FOXK2–PDGFA Macrophage Axis

Microplastics are increasingly detected in the atmosphere and human tissues, yet their long-term effects on lung biology remain unclear. Here, we identified multiple microplastic polymers in human lung tissues using pyrolysis–gas chromatography/mass spectrometry (Py-GC/MS). Using a chronic inhalation model with environmentally relevant concentrations, we show that microplastic exposure induces progressive pulmonary fibrosis in a particle size–dependent manner, with nanoscale particles producing stronger fibrogenic effects than micron-scale particles. Single-cell transcriptomics revealed expansion of Fabp5⁺ interstitial macrophages and early fibroblast activation specifically following nanoscale exposure. Cell–cell communication analysis identified PDGFA–PDGFRA signaling as a key mediator of macrophage–fibroblast interactions. Mechanistically, nanoscale microplastics activated a Fabp5–FOXK2–PDGFA transcriptional axis in macrophages, whereas micron-scale particles showed minimal activation. Fabp5 silencing suppressed this pathway and attenuated pulmonary fibrosis, revealing a macrophage-driven mechanism linking inhaled microplastics to fibrotic lung remodeling.