Iron-Rich Particles Drive Pulmonary Toxicity of Coal Combustion-Derived Fine Particles via Transferrin Receptor-Mediated Ferroptosis

Coal-derived fine particles (FPs, <1 μm) are highly reactive and compositionally heterogeneous, yet their toxicity mechanisms remain poorly understood. Using single-particle ICP-TOF-MS, we profiled metal(loid)s in FPs from ten representative coal-fired power plants across China. Quantification showed that 57 ± 9% of FPs were multimetal(loid) (mmFPs), 84 ± 9% of which were Al/Si/Fe-rich and carried most toxic metals. Toxicology assays identified that Fe-rich FPs and associated toxic metals (Cr, Mn, and Pb) could be important contributors to cellular injury, accompanied by oxidative stress and in vitro transcriptomic enrichment of ferroptosis, inflammation, and small-cell lung cancer-related signaling pathways. As an easily separable Fe-rich FP fraction, magnetic FPs comprised only 15.8% of the mass yet contributed 74.2% of oxidative stress and 88.5% of the cytotoxicity. In vitro and in vivo experiments revealed their transferrin receptor (TFRC)-mediated uptake induced ferroptosis and pulmonary injury, which could be attenuated by a TFRC inhibitor. These results suggest Fe-rich FPs (together with associated toxic metals) as the significant contributor of coal-combustion FP toxicity and provide the mechanistic evidence pinpointing Fe-rich particles as key determinants.