Ferritinophagy Mediated by Oxidative Stress-Driven Mitochondrial Damage Is Involved in the Polystyrene Nanoparticles-Induced Ferroptosis of Lung Injury.

Abstract

Nanoplastics are a common type of contaminant in the air. However, no investigations have focused on the toxic mechanism of lung injury induced by nanoplastic exposure. In the present study, polystyrene nanoplastics (PS-NPs) caused ferroptosis in lung epithelial cells, which could be alleviated by ferrostatin-1, deferoxamine, and N-acetylcysteine. Further investigation found that PS-NPs disturbed mitochondrial structure and function and triggered autophagy. Mechanistically, oxidative stress-derived mitochondrial damage contributed to ferroptosis, and autophagy-dependent ferritinophagy was a pivotal intermediate link, resulting in ferritin degradation and iron ion release. Furthermore, inhibition of ferroptosis using ferrostatin-1 alleviated pulmonary and systemic toxicity to reverse the mouse lung injury induced by PS-NPs inhalation. Most importantly, the lung-on-a-chip was further used to clarify the role of ferroptosis in the PS-NPs-induced lung injury by visualizing the ferroptosis, oxidative stress, and alveolar-capillary barrier dysfunction at the organ level. In summary, our study indicated that ferroptosis was an important mechanism for nanoplastics-induced lung injury through different lung cells, mouse inhalation models, and three-dimensional-based lung-on-a-chip, providing an insightful reference for pulmonary toxicity assessment of nanoplastics.