Dual-TargetingTrxR-EGFR Alkynyl-Au(I) Gefitinib ComplexInduces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradationof GPX4

Gefitinib exhibits significant clinical efficacy in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) sensitive mutations. However, its efficacy is severely limited by acquired resistance. Herein, we designed and synthesized a series of dual-targeting thioredoxin reductase (TrxR)-EGFR gold complexes by attaching a gold ligand to the parent structure of gefitinib, 4-anilinoquinazoline. Among them, <b>L1Au2</b> exhibited significant activity against both gefitinib-sensitive and resistant lung cancers, effectively inhibiting tumor proliferation and promoting apoptosis. Mechanistically, <b>L1Au2</b> effectively inhibits TrxR and EGFR both in vitro and in vivo. Additionally, <b>L1Au2</b> promotes the degradation of GPX4 protein via autophagolysosomal and proteasomal pathways, leading to ferroptosis. Notably, <b>L1Au2</b> also induces endoplasmic reticulum stress (ERS) and triggers immunogenic cell death (ICD). In conclusion, this study provides an innovative strategy for overcoming gefitinib resistance in lung cancer by utilizing dual-targeting TrxR-EGFR alkynyl-Au(I) gefitinib derivatives, thereby offering a new approach for treating gefitinib-resistant lung cancer.