Pancreatic cancer remains one of the most lethal malignancies, with poor survival rates largely attributed to intrinsic and acquired resistance to chemotherapy. While ferroptosis has emerged as a promising therapeutic avenue for overcoming treatment resistance, the molecular mechanisms that enable pancreatic cancer cells to evade this iron-dependent form of cell death remain incompletely understood.

A new study published in Genes & Diseases by researchers from Chinese Academy of Medical Sciences and Peking Union Medical College identifies a previously unrecognized epigenetic mechanism by which the iron-responsive protein IRP1 cooperates with the transcription factor ARID3A to suppress ferroptosis and promote chemoresistance in pancreatic cancer.

The researchers found that both IRP1 and ARID3A are highly expressed in pancreatic cancer tissues and are strongly associated with poor responses to chemotherapy and unfavorable patient survival. Functional studies demonstrated that elevated levels of either protein significantly enhance tumor cell proliferation and resistance to gemcitabine, whereas genetic silencing of IRP1 or ARID3A restores chemosensitivity and suppresses tumor growth. These findings identify the IRP1–ARID3A signaling axis as a key determinant of therapeutic response in pancreatic cancer.

Mechanistic investigations revealed that intracellular iron accumulation triggers the nuclear translocation of IRP1, where it interacts directly with ARID3A. The resulting IRP1–ARID3A complex binds to the promoter region of cytoglobin (CYGB), a gene known to protect cells from oxidative stress and regulate ferroptosis. Rather than directly repressing gene transcription, the complex remodels chromatin by reducing promoter accessibility, thereby suppressing CYGB expression through an epigenetic mechanism.

Loss of CYGB profoundly alters cellular redox homeostasis. Pancreatic cancer cells exhibit reduced lipid peroxidation, diminished accumulation of reactive oxygen species, and enhanced resistance to ferroptotic cell death, allowing them to survive chemotherapy-induced oxidative stress. Restoration of CYGB expression or disruption of the IRP1–ARID3A complex reverses these effects, sensitizing tumor cells to ferroptosis and significantly improving the efficacy of chemotherapeutic treatment.

The study further demonstrates the therapeutic potential of targeting this pathway in preclinical models. Inhibition of IRP1 or ARID3A, particularly when combined with ferroptosis-inducing agents or conventional chemotherapy, markedly suppresses tumor progression and enhances anti-tumor responses. These findings suggest that overcoming ferroptosis resistance may represent an effective strategy for improving outcomes in pancreatic cancer patients who fail to respond to standard treatment.

Collectively, this work identifies the IRP1–ARID3A–CYGB axis as a central regulator of ferroptosis resistance and chemotherapy failure in pancreatic cancer. By linking iron metabolism, chromatin remodeling, and regulated cell death, the study uncovers a novel therapeutic vulnerability and provides a strong rationale for combining epigenetic modulation with ferroptosis-based therapies to combat one of the most treatment-resistant human cancers.


Reference
Title of Original Paper: IRP1/ARID3A complex promotes pancreatic cancer chemoresistance by suppressing CYGB-related ferroptosis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101866

Funding Information:
The Beijing Natural Science Foundation (China) (No. 7232127)
The National Natural Science Foundation of China (No. 82173074)
The National High Level Hospital Clinical Research Funding (China) (No. 2022-PUMCH-B-004; No. 2022-PUMCH-D-001)
The CAMS Innovation Fund for Medical Sciences (China) (No. 2021-I2M-1–002)
The Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2018PT32014)
The Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (No. GZC20240146)
The CAMS Innovation Fund for Medical Sciences (China) (No. 2023-I2M-2-002)

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