Vanadates inhibit non-small cell lung cancer through modulation of ferroptosis mediated by the CBS-CPS1 axis

Abstract

Lung cancer remains the leading cause of cancer mortality, where intrinsic and acquired resistance to cisplatin-based chemotherapy constitutes a major therapeutic challenge in non-small cell lung cancer (NSCLC). Previous studies suggested that vanadium might represent a promising platinum-alternative therapeutic strategy for NSCLC through a unique chemical reaction pattern, though the regulatory networks remain incompletely characterized. Integrated pharmacological screening with cell death pathway inhibitors and transcriptomic profiling revealed that vanadium compounds suppress NSCLC progression by triggering ferroptosis, a process governed by cystathionine β-synthetase (CBS)-mediated regulatory mechanisms. CBS knockdown promoted intracellular Fe²⁺ accumulation, elevated lipid ROS levels, and increased MDA content, ultimately leading to the inhibition of cell growth and proliferation both in vitro and in vivo. Conversely, ICP-MS analysis revealed that CBS overexpression substantially decreased cellular iron uptake. The CBS-specific inhibitor AOAA demonstrated potent synergistic effects with vanadates in suppressing NSCLC cell growth. Furthermore, CoIP-MS identified CPS1 as a potential direct interacting protein of CBS. Remarkably, CPS1 complementation in shCBS NSCLC cells attenuated the key indicators of ferroptosis while restoring cell growth and proliferation. Collectively, our study systematically elucidated the underlying mechanisms by which vanadates inhibit NSCLC progression and defined the functional significance of the CBS-CPS1 axis, providing novel therapeutic insights for advancing vanadium-based metallodrugs in clinical oncology.