PCK2 Inhibition Reverses Cisplatin Resistance of Non-Small Cell Lung Cancer by Triggering Ferroptosis.

Authors

Jing Liu, Ziyan Wang, Chen Gu, Yili Chen, Yang Yang, Jianjie Zhu, Yihua Zhang, Yuna Shao, Xiaodong Pang, Yujie Ge, Huiwen Qian, Jian-An Huang, Zeyi Liu, Yuanyuan Zeng, Cheng Ji

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 16. Pages e72195. Aug 31, 2026.

Abstract

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.

PMID:
42599961
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.