Nuclear accumulation of stabilized SPDEF drives nanoplastic-induced lung adenocarcinoma progression through sustaining inflammation via TRIB3–c-Fos signaling

Polystyrene nanoplastics (PS-NPs) have been extensively studied as emerging environmental pollutants and considered as potential risk factors for lung cancer. However, the significance of chronic exposure to PS-NPs and the molecular mechanisms by which they influence lung cancer progression have been insufficiently explored. Here, lung adenocarcinoma (LUAD) cells were chronically exposed to 20 nm PS-NPs at a concentration approximating estimated weekly human environmental intake for up to 80 passages. Progressive intracellular accumulation of PS-NPs was observed, accompanied by increased malignant proliferation starting from passage 50. In a murine lung cancer model, continuous PS-NPs exposure significantly accelerated tumor progression. Integrating transcriptomic data from nanoplastic-exposed models and human lung cancer, we identified SPDEF as a potential key regulator of PS-NPs-driven progression. SPDEF expression progressively increased in vitro and was markedly elevated in tumors from exposed mice. These findings position SPDEF as an oncogenic driver in response to PS-NPs exposure. Functional studies using SPDEF-overexpressing and SPDEF-knockdown LUAD cells further demonstrated the critical roles of SPDEF in mediating PS-NPs-induced proliferation. Mechanistically, chronic PS-NPs exposure enhanced the nuclear stabilization of SPDEF, leading to its accumulation and subsequently increasing its transcriptional activity. This resulted in upregulated expression of target TRIB3, which in turn promoted the protein-protein interaction between TRIB3 and c-Fos, a key mediator of inflammation and oxidative stress. The SPDEF–TRIB3–c-Fos signaling, specifically activated by chronic PS-NPs exposure, triggered a persistent inflammatory response and ultimately accelerated LUAD progression. This study offers new theoretical insights and identifies potential therapeutic targets for reducing LUAD risk associated with environmental nanoplastic exposure. Environmental implication Environmental factors play a critical role in cancer progression. With the increasing prevalence of emerging pollutants such as polystyrene nanoplastics (PS-NPs), continuous assessment of their health risks has become imperative. This study investigates the effects of chronic, low-dose PS-NPs exposure using long-term cell cultures and a lung cancer mouse model. The findings demonstrate that sustained PS-NPs exposure accelerates lung adenocarcinoma progression through the SPDEF–TRIB3–c-Fos signaling, which drives persistent inflammation. These insights reveal a previously unrecognized mechanism underlying NP-associated cancer risk and highlight potential therapeutic targets.