Inhalation exposure to cationic nanoplastic induces ferroptosis in the lung by perturbing core circadian transcription factors Bmal1

The increasing concentration of nanoplastics in the atmosphere has raised significant concerns regarding their biological toxicity. The toxicity of nanoplastics is often influenced by the surface charge they acquire in complex atmospheric environments. However, the mechanisms underlying lung toxicity from positively charged nanoplastics remain poorly understood, and effective pharmacological prevention and treatment strategies are lacking. This study aimed to investigate the pulmonary toxicity mechanisms of 100 nm amino-modified polystyrene nanoplastics (APS-NPs) using in vivo and in vitro models. In vivo, mice exposed to APS-NPs via inhalation exhibited oxidative stress and ferroptosis in lung tissues. Transcriptomic analysis revealed 566 differentially expressed mRNAs in the APS-NPs group compared to controls, primarily associated with 69 KEGG pathways. These findings suggest that APS-NPs induce ferroptosis in pulmonary tissues by inhibiting the Bmal1/Nrf2/HO-1 signaling cascade. In vitro, APS-NPs-induced ferroptosis in MLE-12 cells was significantly exacerbated by silencing the Bmal1 gene. Intriguingly, pre-treatment with mogrol (Mg), a natural Bmal1 agonist, protected against APS-NPs-induced lung toxicity. Our study provides new insights into the mechanisms of nanoplastic-induced lung toxicity, highlighting the role of disrupted circadian transcription factors like Bmal1 in driving ferroptosis and proposing potential intervention strategies to mitigate lung damage.