{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:16:22Z","timestamp":1790288182572,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC110\u20102320\u2010B\u2010037\u2010025\u2010MY3"],"award-info":[{"award-number":["NSTC110\u20102320\u2010B\u2010037\u2010025\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004694","name":"Kaohsiung Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004694","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ferroptosis has been characterised by disruption of the cell membrane through iron\u2010related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR\u2010TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis\u2010associated tyrosine kinase (<jats:italic>AATK<\/jats:italic>) mRNA expression in gefitinib\u2010resistant PC9 (PC9\u2010GR) cells, which were found to be more susceptible to ferroptosis inducers. An in\u2010depth analysis of publicly available datasets revealed that downregulation of <jats:italic>AATK<\/jats:italic> mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK\u2010sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3\u2010induced cell death in PC9\u2010GR and HCC827\u2010GR cells. Compared to PC9 cells, PC9\u2010GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3\u2010induced ferroptosis in PC9\u2010GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe<jats:sup>2+<\/jats:sup>) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe<jats:sup>2+<\/jats:sup> levels in PC9\u2010GR cells. Inhibition of AATK downregulation\u2010induced iron accumulation decreased RSL3\u2010induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR\u2010TKI\u2010resistant lung cancer cells. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6393","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T02:25:12Z","timestamp":1738031112000},"page":"422-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Downregulation of <scp>AATK<\/scp> enhances susceptibility to ferroptosis by promoting endosome recycling in gefitinib\u2010resistant lung cancer cells"],"prefix":"10.1002","volume":"265","author":[{"given":"Wei\u2010Chang","family":"Lee","sequence":"first","affiliation":[{"name":"Graduate Institute of Medicine Kaohsiung Medical University  Kaohsiung 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