To investigate the protective and preventive effects of Euphorbia helioscopia aqueous extract on the progression of chronic obstructive pulmonary disease(COPD) to lung cancer in mice and to explore its underlying molecular mechanisms.Methods:Sixty mice were randomly divided into a normal group，a model group，and three E.helioscopia aqueous extract low-，medium-，and high-dose groups(0.9，1.8，and 3.6 mg/kg).A COPD-lung cancer transformation model was established using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) combined with lipopolysaccharide(LPS).Samples were collected at weeks 13 and 26.The component content in the extract was determined by UV spectrophotometry.Lung function parameters，including peak expiratory flow(PEF) and pause(Pau)，were measured using a lung function analyzer.White blood cell counts in peripheral blood and bronchoalveolar lavage fluid(BALF) were assessed using an automated hematology analyzer.Lung tissue morphology was examined via hematoxylin and eosin(HE) staining.Immunohistochemistry(IHC) was used to detect the expression of thyroid transcription factor-1(TTF-1)，neuron-specific enolase(NSE)，and proliferating cell nuclear antigen(PCNA).Quantitative real-time PCR(qRT-PCR) was employed to measure the mRNA levels of tumor necrosis factor-alpha(TNF-α) and interleukin-6(IL-6).Western blot was performed to assess protein expression of nuclear factor-κB(NF-κB)，phosphorylated NF-κB(p-NF-κB)，signal transducer and activator of transcription 3(STAT3)，phosphorylated STAT3(p-STAT3)，B-cell lymphoma-2(Bcl-2)，and Bcl-2-associated X protein(Bax).Results:The E.helioscopia aqueous extract contained approximately 16.32% total flavonoids and 7.79% total phenolic acids，with the lowest content found in terpenoids.Compared to the model group，the extract improved lung function indicators(PEF，Pau)，reduced white blood cell counts in peripheral blood and BALF，alleviated histopathological changes and carcinogenesis in lung tissue，downregulated TNF-α and IL-6 mRNA levels，increased Bcl-2 expression，and decreased the expression of TTF-1，NSE，PCNA，p-NF-κB，p-STAT3，and Bax.Conclusion:E.helioscopia aqueous extract exerts therapeutic effects on the progression of COPD to lung cancer in mice，potentially through suppression of inflammatory responses，regulation of tumor proliferation-related proteins，and modulation of the NF-κB/STAT3 and Bcl-2/Bax signaling pathways