The CHPT-pSTAT3-SLC7A11 signaling axis controls progression and ferroptosis susceptibility of pancreatic cancer
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Updated: Jan 9, 2026

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Jianhui Yang1, Jiang Liu1, Zeyin Rong1
1Department 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.
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.
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