Ferroptosis Suppression by the M6A Reader IGF2BP1 Underlies Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
- 1Department of Pancreato‐Biliary Surgery The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong China
- 2Department of Medical Oncology The Second Affiliated Hospital of Guangzhou Medical University Guangzhou Medical University Guangzhou Guangdong China
- 3Department of Hepatobiliary Pancreatic Tumor Center Chongqing University Cancer Hospital Chongqing China
Abstract
Aims: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with poor prognosis, and gemcitabine‐based chemotherapy remains the standard first‐line treatment. However, the rapid emergence of chemoresistance limits its efficacy. Elucidating the molecular mechanisms underlying gemcitabine resistance is critical for improving therapeutic outcomes.
Approaches & Results: By integrating transcriptomic profiling of gemcitabine‐resistant PDAC cells, patient‐derived xenografts (PDXs), and pretreatment clinical biopsy specimens, we identified the m6A reader IGF2BP1 as a key determinant of both intrinsic and acquired gemcitabine resistance. Mechanistically, IGF2BP1 directly binds m6A‐modified FTH1 mRNA and cooperates with G3BP1‐mediated stress granule sequestration to enhance FTH1 transcript stability under chemotherapeutic stress. The stabilized FTH1 maintains intracellular iron homeostasis, limits lipid peroxidation, and suppresses ferroptosis, thereby conferring chemoresistance. Pharmacological inhibition of IGF2BP1 with BTYNB partially disrupted this regulatory axis, restored ferroptotic susceptibility, and synergistically enhanced gemcitabine efficacy in resistant PDX models without overt toxicity.
Conclusions: Collectively, this study uncovers a previously unrecognized epitranscriptomic mechanism linking m6A‐dependent RNA stabilization, stress granule dynamics, and ferroptosis suppression in PDAC. By identifying IGF2BP1 as a potential biomarker of gemcitabine response and a therapeutically actionable target, these findings provide a preclinical rationale for IGF2BP1‐targeted combination strategies to overcome gemcitabine resistance in PDAC.
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BibTeX
@article{zhu2026ferroptosis,
title = {{Ferroptosis Suppression by the M6A Reader IGF2BP1 Underlies Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma}},
author = {Ying‐Qin Zhu and Yue Huang and Jing‐Yuan Ye and Si‐Yuan Lu and Zhi‐De Liu and Ming‐Jian Ma and De‐Liang Fang and Zi‐Yi Zhao and Jin‐Zhao Xie and Jiao Chen and Xiao‐Yu Yin},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77048},
url = {https://doi.org/10.1002/advs.77048},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ferroptosis Suppression by the M6A Reader IGF2BP1 Underlies Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
AU - Ying‐Qin Zhu
AU - Yue Huang
AU - Jing‐Yuan Ye
AU - Si‐Yuan Lu
AU - Zhi‐De Liu
AU - Ming‐Jian Ma
AU - De‐Liang Fang
AU - Zi‐Yi Zhao
AU - Jin‐Zhao Xie
AU - Jiao Chen
AU - Xiao‐Yu Yin
PY - 2026
DA - 2026/08/10
JO - Advanced Science
DO - 10.1002/advs.77048
UR - https://doi.org/10.1002/advs.77048
AB - Aims: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with poor prognosis, and gemcitabine‐based chemotherapy remains the standard first‐line treatment. However, the rapid emergence of chemoresistance limits its efficacy. Elucidating the molecular mechanisms underlying gemcitabine resistance is critical for improving therapeutic outcomes. Approaches & Results: By integrating transcriptomic profiling of gemcitabine‐resistant PDAC cells, patient‐derived xenografts (PDXs), and pretreatment clinical biopsy specimens, we identified the m6A reader IGF2BP1 as a key determinant of both intrinsic and acquired gemcitabine resistance. Mechanistically, IGF2BP1 directly binds m6A‐modified FTH1 mRNA and cooperates with G3BP1‐mediated stress granule sequestration to enhance FTH1 transcript stability under chemotherapeutic stress. The stabilized FTH1 maintains intracellular iron homeostasis, limits lipid peroxidation, and suppresses ferroptosis, thereby conferring chemoresistance. Pharmacological inhibition of IGF2BP1 with BTYNB partially disrupted this regulatory axis, restored ferroptotic susceptibility, and synergistically enhanced gemcitabine efficacy in resistant PDX models without overt toxicity. Conclusions: Collectively, this study uncovers a previously unrecognized epitranscriptomic mechanism linking m6A‐dependent RNA stabilization, stress granule dynamics, and ferroptosis suppression in PDAC. By identifying IGF2BP1 as a potential biomarker of gemcitabine response and a therapeutically actionable target, these findings provide a preclinical rationale for IGF2BP1‐targeted combination strategies to overcome gemcitabine resistance in PDAC.
SN - 2198-3844
ER -