Research progress of pancreatic cancer based on ferroptosis-cuproptosis interaction (Review).

Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and pancreatic ductal adenocarcinoma (PDAC) constitutes the overwhelming majority of histological subtypes. KRAS mutation-driven metabolic reprogramming renders PDAC highly dependent on metal ion homoeostasis and antioxidant systems, thereby providing a novel rationale for therapeutic strategies targeting ferroptosis and cuproptosis. Ferroptosis is a form of regulated cell death caused by the excessive accumulation of iron-dependent lipid peroxidation, whereas cuproptosis is a newly characterised mode of cell death triggered by copper binding to mitochondrial lipoylated proteins, leading to proteotoxic stress. In PDAC, these two forms of cell death are not independent; rather, they interact through multiple metabolic and stress-response pathways. This review systematically summarizes the core molecular mechanisms of ferroptosis and cuproptosis, with particular emphasis on their crosstalk mediated by key nodes, including glutathione, mitochondria, the tricarboxylic acid cycle, iron-sulfur clusters and glutathione peroxidase 4. It further analyses how tumour microenvironmental factors, such as KRAS mutation, cancer-associated fibroblasts, hypoxia and epithelial-mesenchymal transition, regulate these two death programmes, and discusses their functional significance in drug resistance, cancer stem cells and the immune microenvironment. Finally, this review outlines PDAC therapeutic strategies based on the coordinated regulation of ferroptosis and cuproptosis, with the aim of providing a theoretical basis for the development of novel synergistic therapies targeting metal-dependent cell death in pancreatic cancer.