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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\u2014known for their established safety and blood\u2013brain barrier (BBB) permeability\u2014offers a promising alternative.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Using Connectivity Map analysis, we identified the antipsychotic agent fluphenazine (Flu) as a potential anti\u2010LUAD 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Flu acts as a lck\/yes\u2010related protein tyrosine kinase (LYN) kinase inhibitor, exerting both anti\u2010proliferative and anti\u2010metastatic 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\u2010regulates glutathione peroxidase 4 (GPX4).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>This study unveils a novel mechanism by which Flu suppresses LUAD through the LYN\u2013FAK\u2013GPX4 axis, supporting CNS drug repurposing and highlighting the value of BBB\u2010penetrant 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70686","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:27:27Z","timestamp":1790814447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct targeting of LYN kinase by fluphenazine triggers ferroptosis to suppress lung adenocarcinoma"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9230-9430","authenticated-orcid":false,"given":"Yuna","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine The First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"Department of Pharmacy The First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"College of Pharmaceutical Sciences Soochow 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