Using the model PM2.5 library strategy, we found that Zn2+ loading on the insoluble cores was the major contributor to model PM2.5-induced cytotoxicity and inflammation in 16HBE cells. Upregulated expression of circ_0008553, a novel circRNA with functions previously unknown, was responsible for the model PM2.5-induced oxidative stress, and subsequent inflammatory response. While the identification of key toxic components in determining the health risk of PM2.5 will benefit the formulation of standard for atmospheric pollutant emission targeting specific pollutants, our findings in clarifying the underlying mechanisms involved in circRNA-mediated regulation of airway oxidative stress and inflammation induced by PM2.5 exposures provide new perspective on the intervention of PM2.5-associated adverse outcomes.