Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.
8 affiliations
- 1Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy.
- 2Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy.
- 3Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
- 4Research Center LURM (Interdepartmental Laboratory of Medical Research), University of Verona, Verona, Italy.
- 5Department of Neurosciences, Biomedicine and Movement Sciences, Section of Anatomy and Histology, University of Verona, Verona, Italy.
- 6Department of Engineering for Innovation Medicine, Section of Biomedicine, University of Verona, Verona, Italy.
- 7Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy. [email protected].
- 8Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy. [email protected].
Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by late diagnosis, rapid progression, and resistance to conventional therapies. Mutations in the tumor suppressor gene TP53 are prevalent in this cancer and have been associated with gain-of-function activities that promote tumor survival. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a potential therapeutic vulnerability. However, the influence of mutant p53 on ferroptosis susceptibility remains poorly understood.Methods
We employed isogenic pancreatic cancer cell models, including CRISPR-Cas9-mediated TP53 Knockout (TP53-KO) and transient overexpression of common mutant TP53 variants, to examine ferroptosis sensitivity. Cell viability, reactive oxygen species accumulation, lipid peroxidation, mitochondrial integrity, and metabolic profiling were assessed following treatment with ferroptosis inducers. Transcriptional changes were analysed by RNA sequencing, and functional contributions of glycolysis and mitochondrial respiration were evaluated using metabolic flux assays. Pharmacological reactivation of wild-type p53 was tested in combination with ferroptosis inducers in vitro and in orthotopic murine models.Results
Deletion of mutant TP53 sensitized pancreatic cancer cells to ferroptosis, accompanied by increased oxidative stress, lipid peroxidation and mitochondrial dysfunction. Mutant TP53 expression preserved mitochondrial integrity and sustained bioenergetic flexibility under ferroptotic stress. Transcriptomic analyses revealed a multi-layered adaptive program, including upregulation of antioxidant and metabolic genes, and activation of PI3K-AKT signaling, which is associated to a selective glycolytic shift to maintain ATP levels. Functional modulation confirmed that glucose supplementation enhanced, whereas glycolytic inhibition impaired, survival under ferroptotic conditions in mutant TP53-expressing cells, but not in TP53-KO cells. Pharmacological reactivation of wild-type p53 disrupted this adaptive network, abrogating glycolytic reprogramming and significantly increasing ferroptotic cell death both in vitro and in vivo.Conclusions
Mutant p53 orchestrates transcriptional and metabolic plasticity that confers ferroptosis resistance in pancreatic cancer. Reactivating wild-type p53 in combination with ferroptosis induction overcomes this resistance, highlighting a therapeutically actionable vulnerability and supporting the development of combinatorial strategies for this aggressive malignancy.
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BibTeX
@article{celesia2026metabolic,
title = {{Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.}},
author = {Adriana Celesia and Filippo Piccoli and Tian Wang and Yushu Hu and Federica Danzi and Antonino Aparo and Barbara Cisterna and Raffaella Pacchiana and Maria Poles and Maria Teresa Scupoli and Claudio Luchini and Stefano Ugel and Massimo Donadelli and Alessandra Fiore},
journal = {Molecular cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02746-y},
url = {https://europepmc.org/article/MED/42902383},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.
AU - Adriana Celesia
AU - Filippo Piccoli
AU - Tian Wang
AU - Yushu Hu
AU - Federica Danzi
AU - Antonino Aparo
AU - Barbara Cisterna
AU - Raffaella Pacchiana
AU - Maria Poles
AU - Maria Teresa Scupoli
AU - Claudio Luchini
AU - Stefano Ugel
AU - Massimo Donadelli
AU - Alessandra Fiore
PY - 2026
DA - 2026/07/01
JO - Molecular cancer
DO - 10.1186/s12943-026-02746-y
UR - https://europepmc.org/article/MED/42902383
AB - Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by late diagnosis, rapid progression, and resistance to conventional therapies. Mutations in the tumor suppressor gene TP53 are prevalent in this cancer and have been associated with gain-of-function activities that promote tumor survival. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a potential therapeutic vulnerability. However, the influence of mutant p53 on ferroptosis susceptibility remains poorly understood.Methods We employed isogenic pancreatic cancer cell models, including CRISPR-Cas9-mediated TP53 Knockout (TP53-KO) and transient overexpression of common mutant TP53 variants, to examine ferroptosis sensitivity. Cell viability, reactive oxygen species accumulation, lipid peroxidation, mitochondrial integrity, and metabolic profiling were assessed following treatment with ferroptosis inducers. Transcriptional changes were analysed by RNA sequencing, and functional contributions of glycolysis and mitochondrial respiration were evaluated using metabolic flux assays. Pharmacological reactivation of wild-type p53 was tested in combination with ferroptosis inducers in vitro and in orthotopic murine models.Results Deletion of mutant TP53 sensitized pancreatic cancer cells to ferroptosis, accompanied by increased oxidative stress, lipid peroxidation and mitochondrial dysfunction. Mutant TP53 expression preserved mitochondrial integrity and sustained bioenergetic flexibility under ferroptotic stress. Transcriptomic analyses revealed a multi-layered adaptive program, including upregulation of antioxidant and metabolic genes, and activation of PI3K-AKT signaling, which is associated to a selective glycolytic shift to maintain ATP levels. Functional modulation confirmed that glucose supplementation enhanced, whereas glycolytic inhibition impaired, survival under ferroptotic conditions in mutant TP53-expressing cells, but not in TP53-KO cells. Pharmacological reactivation of wild-type p53 disrupted this adaptive network, abrogating glycolytic reprogramming and significantly increasing ferroptotic cell death both in vitro and in vivo.Conclusions Mutant p53 orchestrates transcriptional and metabolic plasticity that confers ferroptosis resistance in pancreatic cancer. Reactivating wild-type p53 in combination with ferroptosis induction overcomes this resistance, highlighting a therapeutically actionable vulnerability and supporting the development of combinatorial strategies for this aggressive malignancy.
SN - 1476-4598
ER -