Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of 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, L1Au2 exhibited significant activity against both gefitinib-sensitive and resistant lung cancers, effectively inhibiting tumor proliferation and promoting apoptosis. Mechanistically, L1Au2 effectively inhibits TrxR and EGFR both in vitro and in vivo. Additionally, L1Au2 promotes the degradation of GPX4 protein via autophagolysosomal and proteasomal pathways, leading to ferroptosis. Notably, L1Au2 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.