Abstract

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains associated with high mortality despite advances in current therapies. Deoxypodophyllotoxin (DPT), a natural lignan derived from Anthriscus sylvestris , has been reported to exhibit antitumor activity in multiple cancer types; however, its molecular mechanism of action in LUAD has not been fully elucidated. In this study, we investigated the antitumor effects of DPT in LUAD and explored the involvement of Forkhead box O1 (FOXO1) signaling. Using LUAD cell lines and a xenograft mouse model, we found that DPT significantly inhibited cell proliferation and migration, induced apoptosis, and suppressed tumor growth in vivo . Mechanistic analyses revealed that FOXO1 was predominantly localized in the cytoplasm of LUAD cells under basal conditions. DPT treatment reduced FOXO1 phosphorylation and promoted its translocation into the nucleus, accompanied by enhanced FOXO1-associated antitumor effects. Functional experiments further supported a contributory role of FOXO1 in mediating the cellular response to DPT. Collectively, these findings demonstrate that DPT suppresses LUAD progression and identify FOXO1 as a mechanistically relevant downstream target of DPT. This study provides new insight into the molecular basis of DPT’s anticancer activity and highlights FOXO1 signaling as an important component of its antitumor mechanism in LUAD.