---
title: "PCK2 inhibition restores cisplatin sensitivity in NSCLC by inducing ferroptosis"
id: "pubmed-42599961"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42599961"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42599961/"
doi: "10.1096/fj.202602464R"
published_at: "2026-08-31T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# PCK2 inhibition restores cisplatin sensitivity in NSCLC by inducing ferroptosis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42599961
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42599961/)
- **DOI:** [10.1096/fj.202602464R](https://doi.org/10.1096%2Ffj.202602464R)
- **Published At:** 2026-08-31T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Non‑small cell lung cancer (NSCLC) comprises approximately **85%** of lung cancers and is commonly treated with platinum‑based chemotherapy; resistance to cisplatin is a major clinical problem. - The metabolic enzyme **PCK2** (phosphoenolpyruvate carboxykinase 2) was identified as significantly **upregulated** in the context of cisplatin resistance and was associated with enhanced resistance to ferroptosis. - Overexpression of **PCK2** promoted resistance to ferroptosis and thereby contributed to **cisplatin chemoresistance** in NSCLC models. - The small molecule **RGB‑286638 free base (RGB)** was found to inhibit **PCK2** expression by directly binding at the R454 site of the protein, leading to activation of ferroptosis in cisplatin‑resistant cells. - Treatment with RGB restored cisplatin sensitivity in both **in vitro** and **in vivo** experimental systems according to the source. - Targeting metabolic reprogramming via **PCK2** inhibition is proposed as a potential therapeutic strategy to overcome cisplatin resistance in NSCLC. - The source reports these principal findings but does not provide experimental details, quantitative outcomes, dosing regimens, safety data, or patient‑level evidence in the abstract; those specifics were not reported in the provided source text.
## Clinical Analysis & Structured Key Points
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PCK2 Inhibition Reverses Cisplatin Resistance of Non-Small Cell Lung Cancer by Triggering Ferroptosis [Jing Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+J&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Ziyan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Z&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Chen Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+C&cauthor_id=42599961)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-2 "Department of Respiratory Medicine, Taixing Second People's Hospital, Taixing, China."), [Yili Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yang Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Jianjie Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+J&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Yihua Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42599961)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-4 "Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yuna Shao](https://pubmed.ncbi.nlm.nih.gov/?term=Shao+Y&cauthor_id=42599961)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-4 "Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Xiaodong Pang](https://pubmed.ncbi.nlm.nih.gov/?term=Pang+X&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yujie Ge](https://pubmed.ncbi.nlm.nih.gov/?term=Ge+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Huiwen Qian](https://pubmed.ncbi.nlm.nih.gov/?term=Qian+H&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Jian-An Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+JA&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Zeyi Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+Z&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Yuanyuan Zeng](https://pubmed.ncbi.nlm.nih.gov/?term=Zeng+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Cheng Ji](https://pubmed.ncbi.nlm.nih.gov/?term=Ji+C&cauthor_id=42599961)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#full-view-affiliation-5 "Department of Pulmonary and Critical Care Medicine, Lung Cancer Center, The First Affiliated Hospital of Soochow University, Suzhou, China.") Affiliations Expand ### Affiliations * 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. * 2 Department of Respiratory Medicine, Taixing Second People's Hospital, Taixing, China. * 3 Institute of Respiratory Diseases, Soochow University, Suzhou, China. * 4 Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China. * 5 Department of Pulmonary and Critical Care Medicine, Lung Cancer Center, The First Affiliated Hospital of Soochow University, Suzhou, China. * PMID: **42599961** * PMCID: [ PMC13475953 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13475953/) * DOI: [ 10.1096/fj.202602464R ](https://doi.org/10.1096/fj.202602464r) Item in Clipboard # PCK2 Inhibition Reverses Cisplatin Resistance of Non-Small Cell Lung Cancer by Triggering Ferroptosis Jing Liu et al. FASEB J. 2026. Show details Display options Display options Format Abstract PubMed PMID FASEB J Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22FASEB+J%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22FASEB+J%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42599961/) . 2026 Aug 31;40(16):e72195. doi: 10.1096/fj.202602464R. ### Authors [Jing Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+J&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Ziyan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Z&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Chen Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+C&cauthor_id=42599961)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-2 "Department of Respiratory Medicine, Taixing Second People's Hospital, Taixing, China."), [Yili Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yang Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Jianjie Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+J&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Yihua Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42599961)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-4 "Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yuna Shao](https://pubmed.ncbi.nlm.nih.gov/?term=Shao+Y&cauthor_id=42599961)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-4 "Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Xiaodong Pang](https://pubmed.ncbi.nlm.nih.gov/?term=Pang+X&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Yujie Ge](https://pubmed.ncbi.nlm.nih.gov/?term=Ge+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Huiwen Qian](https://pubmed.ncbi.nlm.nih.gov/?term=Qian+H&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China."), [Jian-An Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+JA&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Zeyi Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+Z&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Yuanyuan Zeng](https://pubmed.ncbi.nlm.nih.gov/?term=Zeng+Y&cauthor_id=42599961)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-1 "Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-3 "Institute of Respiratory Diseases, Soochow University, Suzhou, China."), [Cheng Ji](https://pubmed.ncbi.nlm.nih.gov/?term=Ji+C&cauthor_id=42599961)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42599961/#short-view-affiliation-5 "Department of Pulmonary and Critical Care Medicine, Lung Cancer Center, The First Affiliated Hospital of Soochow University, Suzhou, China.") ### Affiliations * 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. * 2 Department of Respiratory Medicine, Taixing Second People's Hospital, Taixing, China. * 3 Institute of Respiratory Diseases, Soochow University, Suzhou, China. * 4 Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China. * 5 Department of Pulmonary and Critical Care Medicine, Lung Cancer Center, The First Affiliated Hospital of Soochow University, Suzhou, China. * PMID: **42599961** * PMCID: [ PMC13475953 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13475953/) * DOI: [ 10.1096/fj.202602464R ](https://doi.org/10.1096/fj.202602464r) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## 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. **Keywords:** Cisplatin; Ferroptosis; NSCLC; PCK2; RGB‐286638 free base. © 2026 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement The authors declare no conflicts of interest. ## Figures [ ![FIGURE 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/13475953/bf8229792c83/FSB2-40-e72195-g002.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/13475953/03bd1e10bd25/FSB2-40-e72195-g002.jpg) ** FIGURE 1 ** Detection of ferroptosis‐related pathway in… ** FIGURE
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