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Here, we report that cepharanthine (CEP), a natural bisbenzylisoquinoline alkaloid, effectively reverses gefitinib resistance through concurrent suppression of the AKT\/P70S6K survival axis and activation of the Stimulator of Interferon Genes (STING)\u2010mediated innate immune pathway. In gefitinib\u2010resistant H1975 cells (EGFR L858R\/T790M), CEP monotherapy significantly inhibited proliferation and induced mitochondrial apoptosis. Notably, CEP synergized with gefitinib to enhance therapeutic efficacy. RNA sequencing and functional validation revealed that CEP activates the STING\/TANK\u2010Binding Kinase 1 (TBK1)\/Interferon Regulatory Factor 3 (IRF3) signaling cascade, resulting in robust production of T\u2010cell chemoattractants C\u2010X\u2010C Motif Chemokine Ligand 9 (CXCL9), C\u2010X\u2010C Motif Chemokine Ligand 10 (CXCL10), and C\u2010C Motif Chemokine Ligand 5 (CCL5). Critically, the STING inhibitor H\u2010151 abolished CEP's antitumor effects in\u00a0vitro. Our findings reveal a novel dual mechanism action of CEP and nominate it as a potential candidate for overcoming TKI resistance in NSCLC.<\/jats:p>","DOI":"10.1111\/cbdd.70298","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T11:31:37Z","timestamp":1777548697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cepharanthine Reverses Gefitinib Resistance in\n                    <scp>NSCLC<\/scp>\n                    by Concurrently Inhibiting\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>P70S6K<\/scp>\n                    Survival Signaling and Activating\n                    <scp>STING<\/scp>\n                    \u2010Mediated Immune Response"],"prefix":"10.1111","volume":"107","author":[{"given":"Li\u2010Ping","family":"Kang","sequence":"first","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong\u2010Tong","family":"Lv","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua\u2010Jing","family":"Huang","sequence":"additional","affiliation":[{"name":"Northeastern University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong 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