Ferroptosis Suppression by the M 6 A Reader IGF2BP1 Underlies Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
Ying‐Qin Zhu, Yue Huang, Jing‐Yuan Ye, Si‐Yuan Lu, Zhi‐De Liu, Ming‐Jian Ma, De‐Liang Fang, Zi‐Yi Zhao, Jin‐Zhao Xie, Jiao Chen, Xiao‐Yu YinABSTRACT
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 m 6 A reader IGF2BP1 as a key determinant of both intrinsic and acquired gemcitabine resistance. Mechanistically, IGF2BP1 directly binds m 6 A‐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 m 6 A‐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.