Ceritinib induces ferroptosis via TRIM21-mediated GLUT1 ubiquitination and AMPK-driven metabolic reprogramming in breast cancer

Although ceritinib, a potent ALK inhibitor, has been clinically approved for the treatment of non-small cell lung Cancer, its potent cytotoxic activity against breast Cancer cells and the underlying mechanisms remain largely unknown. We show that ceritinib inhibits proliferation and induces Ferroptosis in breast cells. Mechanistically, ceritinib downregulates GLUT1, impairing glycolysis, inducing energy stress, and activating AMPK signaling. Activated AMPK promotes ferritinophagy, leading to iron accumulation, lipid peroxidation, and redox imbalance, ultimately triggering Ferroptosis. Rescue experiments demonstrate that GLUT1 overexpression or AMPK inhibition attenuates these effects, confirming the role of the GLUT1-AMPK axis. At the molecular level, ceritinib promotes TRIM21-mediated ubiquitination and proteasomal degradation of GLUT1 through direct binding. In vivo, ceritinib suppresses tumor growth, while GLUT1 knockdown reduces its efficacy and ferroptotic response. These findings reveal a novel mechanism whereby ceritinib induces Ferroptosis via GLUT1 downregulation and AMPK-dependent ferritinophagy, supporting its potential repurposing for breast Cancer therapy.