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This treatment resistance is a key factor affecting the efficacy of TKIs and a major bottleneck in cancer treatment. The potential underlying cause may be closely related to tumor cell metabolic reprogramming. In this study, we established an EGFR\u2010mutant lung cancer mouse model, isolating and culturing tumor primary cells to explore the cellular and molecular mechanisms of EGFR\u2010mutant lung cancer. Using techniques such as super\u2010resolution microscopy and RNA\u2010seq, we qualitatively and quantitatively analyzed the morphological changes of mitochondria within tumor cells following TKI treatment. Our results indicate that mitochondrial dynamics are remodeled toward increased mitochondrial fission during the early phase of TKI treatment. Furthermore, pharmacological inhibition of mitochondrial fission further sensitizes tumor cells to EGFR\u2010TKIs. Additionally, disrupting oxidative phosphorylation metabolism can increase the sensitivity of tumor cells to TKI treatment and reverse tumor cell resistance to TKI. Overall, these findings suggest that the metabolic reprogramming of mitochondrial OXPHOS in tumor cells mediates energy stress adaptation, altering their response to TKI treatment and providing new metabolic therapeutic targets to overcome EGFR\u2010TKI resistance.<\/jats:p>","DOI":"10.1111\/cas.70488","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T11:36:21Z","timestamp":1786620981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Morphology Dynamics Remodel Metabolism and Affect\n                    <scp>TKI<\/scp>\n                    Sensitivity in\n                    <scp>EGFR<\/scp>\n                    \u2010Mutated Lung Cancer"],"prefix":"10.1111","author":[{"given":"Yu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Sheng Jing Hospital, China Medical University  Shenyang Liaoning China"},{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University  Guangzhou P. 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