<scp>PCK2</scp> Inhibition Reverses Cisplatin Resistance of Non‐Small Cell Lung Cancer by Triggering Ferroptosis

Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers, with platinum-based chemotherapy as the main treatment. Ferroptosis has been implicated in cancer chemoresistance, yet the molecular mechanisms linking metabolic reprogramming to ferroptosis-mediated 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-286638 free base (RGB) inhibits PCK2 expression by directly binding to its R454 site to activate ferroptosis in cisplatin-resistant cells and restores cisplatin sensitivity both in vitro and in vivo. Targeting PCK2 with RGB provides a promising strategy to overcome chemoresistance, facilitating improved clinical interventions for NSCLC.