PM2.5 Induce Endothelial‐Mesenchymal Transition and Cardiac Fibrosis via the NCOA4‐Mediated Ferritinophagy

Epidemiological evidence has indicated a strong association between fine particulate matter (PM2.5) exposure and adverse cardiac outcomes, including dysfunction and fibrosis. However, the underlying mechanisms remain unclear. In this study, the chemical species-specific translocation of PM2.5 is investigated to the heart and its associated toxicological mechanisms. It is found that PM2.5-derived iron (Fe)-containing particles, particularly magnetite, are specifically enriched in the hearts of mice, with Fe content in individual particles increasing progressively along the path from the lungs through serum to the heart. Notably, molecular dynamics simulations demonstrated that Fe-containing particles can form complexes with the key ferritinophagy regulator (nuclear receptor co-activator 4 [NCOA4]), thereby altering its structure and function. Further analyses confirmed that PM2.5 upregulated NCOA4 expression in endothelial cells, which promoted the binding of transcription factor Kruppel-like factor 5 to transforming growth factor beta 1 promoter, driving endothelial-to-mesenchymal transition (EndMT) in vitro and in vivo. Additionally, PM2.5-treated endothelial cells facilitated the transformation of cardiac fibroblasts through paracrine signaling, leading to extracellular matrix production and cardiac fibrosis. Collectively, these findings reveal a previously unrecognized mechanism by which PM2.5-derived Fe-containing particles can trigger EndMT and cardiac fibrosis via ferritinophagy, with important implications for understanding the cardiovascular risks associated with air pollution.