Metabolic Plasticity Underlies Ferroptosis Resistance Driven by Mutant p53 in Pancreatic Ductal Adenocarcinoma

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.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. 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.