Direct targeting of LYN kinase by fluphenazine triggers ferroptosis to suppress lung adenocarcinoma

Abstract Background and Purpose Lung adenocarcinoma (LUAD) is an aggressive malignancy with a poor prognosis. Current therapies often cause significant side effects and result in poor patient tolerance, underscoring the need for safer and more efficient treatment strategies. Repurposing central nervous system (CNS) drugs—known for their established safety and blood–brain barrier (BBB) permeability—offers a promising alternative. Experimental Approach Using Connectivity Map analysis, we identified the antipsychotic agent fluphenazine (Flu) as a potential anti‐LUAD candidate. We then investigated the mechanism of action of Flu in LUAD, including its target protein, binding site and downstream signalling pathways, as well as its induction effect on ferroptosis in LUAD cells. Key Results Flu acts as a lck/yes‐related protein tyrosine kinase (LYN) kinase inhibitor, exerting both anti‐proliferative and anti‐metastatic effects in LUAD. Leu253 of LYN was identified as a critical binding site for Flu. Notably, LYN is highly expressed in lung cancer. Further investigation revealed that Flu induces ferroptosis in LUAD cells; mechanistically, Flu directly inhibits LYN, attenuates downstream focal adhesion kinase (FAK) signalling and significantly down‐regulates glutathione peroxidase 4 (GPX4). Conclusion and Implications This study unveils a novel mechanism by which Flu suppresses LUAD through the LYN–FAK–GPX4 axis, supporting CNS drug repurposing and highlighting the value of BBB‐penetrant drugs for LUAD treatment. Our findings identify LYN as a new therapeutic target and Flu as a candidate drug for targeted ferroptosis induction in LUAD.