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  3. Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis

Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis

  • Cell Rep Med. 2025 Feb 18;6(2):101928. doi: 10.1016/j.xcrm.2025.101928.
Xuqing Shen 1,  Yueyue Chen 1,  Yingying Tang 1,  Ping Lu 1,  Mingzhu Liu 1,  Tiebo Mao 2,  Yawen Weng 1,  Feier Yu 1,  Yimei Liu 1,  Yujie Tang 3,  Liwei Wang 4,  Ningning Niu 5,  Jing Xue 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, China. Electronic address: yujietang@shsmu.edu.cn.
  • 4 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: liweiwang@shsmu.edu.cn.
  • 5 State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: niuningning@shsmu.edu.cn.
  • 6 State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jingxue@sjtu.edu.cn.
PMID: 39879992 DOI: 10.1016/j.xcrm.2025.101928
Abstract

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and Ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to Ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced Ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent Ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Keywords

PDAC; combination therapy; epigenetic remodeling; ferroptosis; pancreatic ductal adenocarcinoma; prolonged glutamine starvation.

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