Chronic Exposure to Polystyrene Nanoplastics Promotes Lung Cancer Progression via Activating Gluconeogenesis and Inhibiting Glycolysis

Nanoplastics (NPs) are emerging as environmental pollutants, yet their long-term impact on lung cancer progression remains largely unexplored. This study explored the influence of extended exposure to polystyrene nanoplastics (PS-NPs) on the growth and movement of A549 lung cancer cells, with particular emphasis on the molecular mechanisms involved in metabolic reprogramming. We demonstrated that prolonged exposure to PS-NPs markedly increased the ability of lung cancer cells to proliferate and migrate. Using an integrated approach combining transcriptomic profiling and C13-labeled glucose flux analysis, we observed that chronic PS-NPs exposure induced metabolic reprogramming characterized by the activation of gluconeogenesis and suppression of glycolysis. Mechanistically, PS-NPs upregulated the gluconeogenic enzyme mitochondrial phosphoenolpyruvate carboxykinase (PCK2) and downregulated enolase-1 (ENO1), a glycolytic enzyme. Notably, knockdown of PCK2 attenuated PS-NPs-induced cell proliferation and migration, underscoring its functional role. We further identified that stress-responsive activating transcription factor-3 (ATF3) serves as a crucial mediator of PCK2 and ENO1 expression. Chromatin immunoprecipitation followed by PCR (ChIP-PCR) confirmed enhanced binding of ATF3 to the promoter regions of PCK2 and ENO1 upon PS-NPs exposure. Silencing ATF3 abolished PS-NPs-induced changes in PCK2 and ENO1 expression and blocked the associated increase in cell proliferation and migration. Clinically, elevated ATF3 and PCK2 expression levels are associated with poor prognosis in patients with lung cancer. In conclusion, chronic exposure to PS-NPs promotes lung cancer progression by inducing metabolic reprogramming via ATF3-mediated regulation of PCK2 and ENO1. These findings shed light on the cancer-promoting capabilities of PS-NPs and identify the ATF3-PCK2 axis as a promising target for lung cancer therapy.