Carbon ions collapse the hypoxic lipid shield to decouple survival from redox vulnerability in NSCLC

Hypoxic non-small cell lung cancer (NSCLC) cells actively remodel lipid metabolism to construct a biochemical shield against lipotoxicity and oxidative stress. This adaptation drives a unidirectional phosphatidylcholine to triacylglycerol conversion with a Z-score of 4.253. While clinically equivalent doses of conventional X-rays (6 Gy) leave the hypoxia-adapted lipidome intact and yield zero significantly altered lipid species, carbon ions radiation markedly rewire the lipidome, significantly displacing 79 lipid species. Combining carbon ions radiation with HIF-1α knockdown amplifies this displacement to 134 altered lipids. This profound structural remodeling is dominated by the exhaustion of phosphatidylcholine and sphingomyelin. Crucially, this metabolic shift occurs without additional acute clonogenic cell kill compared to carbon ions alone. This effectively decouples metabolic disruption from immediate reproductive death. Untargeted metabolomics confirms the concurrent collapse of mitochondrial electron transport and glutathione buffering. Carbon ions radiation effectively abrogate the hypoxic lipid shield. The resulting metabolically compromised survivor subpopulation, stripped of its antioxidant defenses, reveals a pronounced vulnerability to lipid peroxidation. Conventional survival-based relative biological effectiveness systematically underestimates this effect. This study provides defined redox-targeted mechanisms for deploying ferroptosis inducers as precision combination therapies in hypoxic solid tumors.