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Here, we uncover FUNDC1\u2010dependent mitophagy as a key protective mechanism in EGFR\u2010mutant non\u2010small cell lung cancer (NSCLC). We discover that nitidine, a bioactive component of the traditional Xihuang Pill formulation, synergises with the EGFR inhibitor osimertinib. Mechanistically, nitidine and osimertinib synergistically disrupt FUNDC1\u2010mediated mitophagy, leading to mitochondrial dysfunction and accumulation of reactive oxygen species in EGFR\u2010mutant NSCLC. We further show that both osimertinib and nitidine decrease HIF\u20101\u03b1 protein levels, thereby downregulating FUNDC1 expression. Nitidine\u2010induced downregulation of HIF\u20101\u03b1 and FUNDC1 depends on the mitochondrial transporter ABCB6. Notably, acquired resistance to osimertinib exhibits adaptive downregulation of FUNDC1, rendering resistant EGFR\u2010mutant NSCLC cells more sensitive to nitidine. Collectively, these findings position nitidine as a promising therapeutic strategy to enhance the efficacy of EGFR inhibitors and overcome osimertinib resistance in EGFR\u2010mutant NSCLC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70685","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T06:56:01Z","timestamp":1779173761000},"source":"Crossref","is-referenced-by-count":0,"title":["Convergent targeting of FUNDC1\u2010dependent mitophagy sensitises and overcomes resistance to EGFR inhibition"],"prefix":"10.1002","volume":"16","author":[{"given":"Fan","family":"Xu","sequence":"first","affiliation":[{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Institute of Clinical Sciences Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology First 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