FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
PCK2 Inhibition Reverses Cisplatin Resistance of Non-Small Cell Lung Cancer by Triggering Ferroptosis.
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Liu Jing, Wang Ziyan, Gu Chen, Chen Yili, Yang Yang, Zhu Jianjie, Zhang Yihua, Shao Yuna, Pang Xiaodong, Ge Yujie, Qian Huiwen, Huang Jian-An, Liu Zeyi, Zeng Yuanyuan, Ji Cheng
Аннотация
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.