TRPV-1-targeted Fe-phenolate network provokes apoptosis and ferroptosis to treat non-small cell lung cancer.

Ferroptosis has emerged as a potential therapeutic target for chemotherapy of cancer. However, non-small cell lung cancer (NSCLC) exhibits high tolerance to ferroptosis due to inherent resistance. To increase NSCLC vulnerability, we present a TRPV1-targeting approach that self-delivers intracellular irons and TRPV1 agonist (N-oleoyldopamine, OLDA) to provoke simultaneous apoptosis and ferroptosis in NSCLC. Intracellular release of OLDA activates TRPV1 channels, triggering Ca2+ overload and mitochondrial/ER stress to induce apoptosis, while Fe3+ ions drive Fenton reactions, depleting GPX4/GSH and elevating lipid peroxides to induce ferroptosis. FeOLDA demonstrated selective cytotoxicity toward A549 NSCLC cells over normal bronchial epithelial BEAS-2B cells. In vivo studies demonstrate that FeOLDA effectively suppresses tumor growth without weight loss or multi-organ toxicity associated with cisplatin. This dual-action platform offers a lung cancer-targeted and efficient strategy for NSCLC treatment.