Cigarette smoke promotes the progression of non-small cell lung cancer by activating ERK1/2-FOXC1 axis to induce epithelial-mesenchymal transition.

BACKGROUND: Smoking is the leading risk factor for the progression of non-small cell lung cancer (NSCLC); however, the specific mechanisms underlying this association remain unclear. Increasing evidence has suggested that elevated forkhead box protein C1 (FOXC1) expression is associated with cancer progression. However, it remains unclear whether smoking promotes NSCLC progression via FOXC1 expression. Therefore, we used in vivo and in vitro models of smoking-associated NSCLC to investigate the role of FOXC1 in NSCLC progression. METHODS: Cell models were established by treating A549 and H1299 cells with cigarette smoke extract (CSE). Rescue experiments were performed by knocking down FOXC1 and administering U0126, a specific inhibitor of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. The cell counting kit-8, 5-Ethynyl-2′-deoxyuridine proliferation, colony formation, and tumor xenograft assays were performed to assess the proliferative capacity of A549 and H1299 cells. Wound healing and Transwell assays were used to evaluate the migratory and invasive capabilities of these cell lines. Western blotting was performed to detect changes in protein expression. RESULTS: CSE significantly enhanced the proliferation, migration, and invasion capacities of A549 and H1299 cells while inducing alterations in epithelial-mesenchymal transition (EMT) markers and cellular morphology. CSE elevated the expression of FOXC1 in both A549 and H1299 cells. Silencing of FOXC1 mitigated the malignant biological behavior and EMT changes induced by CSE. Additionally, the ERK1/2 signaling pathway was activated in A549 and H1299 cells following CSE treatment. The application of the ERK1/2 pathway inhibitor U0126 reversed the CSE-induced increase in FOXC1 expression and the associated malignant behavior of these cells. CONCLUSIONS: CSE upregulates FOXC1 expression by activating the ERK1/2 signaling pathway, thereby facilitating NSCLC progression. These findings identify novel potential targets for the diagnosis and treatment of smoking-related NSCLC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-026-04227-0.