Navigating the complexities of ferroptosis in pancreatic ductal adenocarcinoma: roles, mechanisms and potential applications

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited therapeutic options and a profoundly immunosuppressive tumor microenvironment (TME). Ferroptosis, a novel form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic avenue by targeting metabolic vulnerabilities in cancer cells. Notably, key ferroptotic pathways in PDAC involve iron accumulation, lipid peroxidation, and oxidative stress. Major defense systems include the System Xc⁻/GSH/GPX4, NAD (P)H-FSP1-CoQH 2 /VKH 2 , DHODH-CoQH 2 , and GCH1-BH4 pathways. Ferroptosis exhibits dual roles in PDAC, demonstrating both tumor-suppressive and oncogenic effects within TME. Ferroptosis-related biomarkers show promise for PDAC diagnosis and prognosis. Novel therapeutic strategies combining ferroptosis inducers with conventional treatments and nanoparticle-based delivery systems have shown encouraging results in preclinical studies. While ferroptosis-based therapies offer potential for PDAC treatment, challenges remain in translating these approaches to clinical practice. Therefore, this review provides a comprehensive synthesis of the mechanistic insights, therapeutic potential, and associated challenges of targeting ferroptosis in PDAC. It is necessary to identify specific biomarkers, mitigate side effects, and elucidate the complex interactions between ferroptosis and TME. Integrating ferroptosis modulation with existing therapies may lead to more effective, personalized treatment strategies for PDAC.