Exposure to ambient particulate matter (PM) is associated with adverse health effects. Yet, due to the complexity of its chemical composition, the molecular effects of PM exposure and the mechanism of PM-mediated toxicity remain largely unknown. Here, we show that water-soluble inorganics such as nitrate and sulfate ions, rather than PM itself, rapidly penetrate the lung surfactant barrier to the alveolar region and perturb gene expression in the lungs. Through high-throughput sequencing of lung adenocarcinoma cells, we find that exposure to nitrate and sulfate ions activates the cholesterol biosynthetic metabolism and induces the expression of genes related to tumorigenesis. Transcriptome analysis of mouse lungs exposed to nitrate/sulfate aerosols reveals interferon gamma-associated immune response. Interestingly, we find that exposure to a nitrate/sulfate mixture leads to a unique gene expression pattern that is not observed when nitrate or sulfate is treated alone. Our work suggests that the water-soluble ions are a potential source of PM-mediated toxicity and provides a roadmap to unveil the molecular mechanism of health hazards from PM exposure.