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.

Ferroptosis; KRAS; Lung cancer; Mitochondria; Pentagalloylglucose (PGG); TRAF6.