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Ferroptosis has been implicated in cancer chemoresistance, yet the molecular mechanisms linking metabolic reprogramming to ferroptosis\u2010mediated cisplatin resistance in NSCLC remain elusive. In this study, we found that phosphoenolpyruvate carboxykinase 2 (PCK2), a metabolic reprogramming enzyme, was significantly upregulated, and its overexpression enhanced ferroptosis resistance, thereby promoting cisplatin chemoresistance. Mechanistically, RGB\u2010286638 free base (RGB) inhibits PCK2 expression by directly binding to its R454 site to activate ferroptosis in cisplatin\u2010resistant cells and restores cisplatin sensitivity both in\u00a0vitro and in\u00a0vivo. 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