2. Academic Validation
  3. The CHPT-pSTAT3-SLC7A11 signaling axis controls progression and ferroptosis susceptibility of pancreatic cancer

The CHPT-pSTAT3-SLC7A11 signaling axis controls progression and ferroptosis susceptibility of pancreatic cancer

  • Transl Oncol. 2026 Jan:63:102624. doi: 10.1016/j.tranon.2025.102624.
Jianhui Yang 1,  Jiang Liu 1,  Zeyin Rong 1,  Zhen Tan 2,  Wei Wang 1,  Qingcai Meng 1,  Miaoyan Wei 1,  Jie Hua 1,  Bo Zhang 1,  Xianjun Yu 1,  Jin Xu 3,  Chen Liang 4
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
  • 2 Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
  • 3 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 4 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 41337814 DOI: 10.1016/j.tranon.2025.102624
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits profound chemoresistance and metastasis, driving its dismal prognosis. Gemcitabine (GEM) resistance remains a critical barrier, necessitating exploration of metabolic regulators like choline phosphotransferase 1 (CHPT1) and Ferroptosis in PDAC therapy.

Method: GEM-resistant PDAC cells were generated through stepwise induction. Metabolomics, RNA Sequencing, and functional assays (CCK-8, EdU, Transwell) identified CHPT's role. CHPT1 and SLC7A11 were genetically modulated using lentiviral vectors. Xenograft models assessed tumor growth.

Results: CHPT1 was downregulated in PDAC tissues and GEM-resistant cells. Restoring CHPT1 suppressed proliferation, migration, and epithelial-mesenchymal transition while enhancing GEM sensitivity. Mechanistically, CHPT1 recruited Phosphatase PTPN1 to dephosphorylate STAT3 at Y705, inhibiting SLC7A11 transcription and triggering Ferroptosis via lipid peroxidation. PTPN1 knockdown abolished CHPT1's tumor-suppressive effects. Combining Ferroptosis inducers (e.g., Erastin) with GEM synergistically inhibited tumor growth in vitro and in vivo.

Conclusion: The CHPT1-pSTAT3-SLC7A11 axis governs ferroptosis-dependent chemoresistance in PDAC. Dual targeting of CHPT1 and Ferroptosis pathways represents a promising strategy to overcome GEM resistance, highlighting metabolic-kinase crosstalk as a therapeutic vulnerability.

Keywords

CHPT1; Chemoresistance; Ferroptosis; Metastasis; Pancreatic cancer.

Figures
Products