Chronic polystyrene microplastics exposure promotes lung adenocarcinoma metastasis through EREG-regulated phosphorylation-dependent NF-κB activation

• Long-term exposure to polystyrene MPs (PS-MPs) significantly enhances migration, invasion, and proliferation of lung adenocarcinoma cells in vitro and promotes tumor metastasis in vivo. • EREG directly interacts with NF-κB signaling pathway core components (p65, p50, and IκBα), inducing their phosphorylation and degradation to drive malignant tumor progression. • Blocking NF-κB signaling with the specific inhibitor BMS-345541 reverses the tumor malignant phenotype induced by PS-MPs. • Clinical analysis confirms that high EREG expression significantly correlates with clinical staging, lymph node metastasis, and poor prognosis in lung adenocarcinoma patients. Plastics, extensively used in daily life, have seen exponential growth in production. However, inadequate recycling and poor biodegradability have led to the rapid accumulation of microplastics (MPs) in the environment, making them pervasive in air, water, and food. As a result, MPs pollution has become one of humanity’s most urgent environmental challenges. Growing evidence indicates that MPs may harm the respiratory system, yet their functional role and the molecular mechanisms in lung adenocarcinoma progression remain to be fully elucidated. To investigate the effects of MPs on lung adenocarcinoma metastasis and growth, we established long-term chronic exposure models. In vitro , cell migration, invasion, colony formation, and CCK‑8 assays were performed; in vivo , a nude mouse metastasis model was used to assess the impact of MPs on malignant behaviors. We further investigated the specific role of EREG and elucidated its underlying mechanisms and downstream signaling pathways through restoration experiment, luciferase reporter assays, co‑immunoprecipitation, and western blotting in differential models. Long-term exposure to polystyrene MPs (PS-MPs) significantly enhances migration, invasion, and proliferation of lung adenocarcinoma cells in vitro and promotes tumor metastasis in vivo . Multi-omics analysis identified epiregulin (EREG) as a key mediator of PS-MP–induced malignant progression. Functional assays confirmed that EREG is essential for PS-MP-driven malignant cell migration, invasion, and proliferation. Enrichment analyses and a pNF-κB-luc reporter assay implicated and validated NF-κB signaling as a critical downstream pathway, with EREG markedly enhancing NF-κB activity. Mechanistically, EREG physically interacts with the NF-κB subunits p65 and p50 as well as IκBα. This interaction promotes the phosphorylation of p65 at Ser536 and IκBα at Ser32/36, leading to IκBα degradation and the consequent activation of NF-κB. Consistently, pharmacological inhibition of NF-κB signaling with BMS-345541, a specific inhibitor, abolished PS-MP–induced oncogenic phenotypes, confirming NF-κB dependence. Clinically, elevated EREG expression correlates with tumor metastasis and poor prognosis in lung adenocarcinoma (LUAD) patients. Chronic PS-MPs exposure promotes lung adenocarcinoma metastasis and progression through the EREG-NF-κB signaling axis, in which EREG interacts with the NF-κB/IκBα complex to provoke its phosphorylation-dependent activation.