TRAF6 promotes the ferroptosis defense through AKT/mitochondria damage in KRAS-driven lung cancer

Ferroptosis, an iron-dependent form of cell death, has emerged as a therapeutic vulnerability in cancer, yet its regulation in kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung cancer remains poorly defined. Here we identified tumor necrosis factor receptor-associated factor 6 (TRAF6) as a critical driver of mitochondria-dependent ferroptosis in KRAS-driven lung cancer. TRAF6 inhibition increased lipid peroxidation, mitochondrial reactive oxygen species (ROS), and Fe²⁺ accumulation, thereby exacerbating mitochondrial damage and enhancing RAS-selective lethal 3 (RSL3)-induced ferroptosis. Genetic silencing of TRAF6 impaired anti-oxidative signaling and markedly suppressed KRAS-mutant lung cancer growth in vivo. Mechanistically, TRAF6 directly interacted with protein kinase B (AKT) to induce the mitochondrion damage and ferroptosis, which was reversed by AKT overexpression or the mitochondrial antioxidant treatment. Through virtual screening, a novel TRAF6-targeted inhibitor pentagalloylglucose (PGG) was identified. PGG bind and degraded TRAF6 efficiently, triggering mitochondrial ferroptosis and robustly suppressing the growth of KRAS-mutant lung cancer, with partial rescue by ferroptosis blockade. These findings uncovered a previously unrecognized TRAF6/AKT-mediated mitochondrial ferroptosis axis and highlighted PGG as a promising candidate against KRAS-mutant lung cancer.