Abstract

Combination therapies are critical for enhancing and prolonging the efficacy of EGFR inhibitors. Here, we uncover FUNDC1-dependent mitophagy as a key protective mechanism in EGFR-mutant non-small 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-mediated mitophagy, leading to mitochondrial dysfunction and accumulation of reactive oxygen species in EGFR-mutant NSCLC. We further show that both osimertinib and nitidine decrease HIF-1α protein levels, thereby downregulating FUNDC1 expression. Nitidine-induced downregulation of HIF-1α and FUNDC1 depends on the mitochondrial transporter ABCB6. Notably, acquired resistance to osimertinib exhibits adaptive downregulation of FUNDC1, rendering resistant EGFR-mutant 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-mutant NSCLC. Key points Nitidine synergises with osimertinib in EGFR-mutant NSCLC. Nitidine and osimertinib converge on HIF-1α/FUNDC1-mediated mitophagy. ABCB6 is required for the nitidine-associated HIF-1α/FUNDC1 response. Adaptive FUNDC1 downregulation sensitises osimertinib-resistant cells to nitidine monotherapy.