Ferroptosis in pancreatic ductal adenocarcinoma: Mechanisms, tumor biology, and therapeutic opportunities.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by persistently poor survival rates and limited effective therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by uncontrolled lipid peroxidation, has recently emerged as a potentially targetable vulnerability in PDAC. In this Review, we synthesize current understanding of the core molecular mechanisms governing ferroptosis, including dysregulated iron metabolism, lipid peroxidation pathways, and failure of antioxidant defense systems. We further discuss the complex regulatory networks that shape ferroptosis sensitivity in PDAC, highlighting the contributions of endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, and DNA damage-associated signaling pathways. Within the broader landscape of PDAC biology, ferroptosis exerts context-dependent and sometimes opposing effects, influencing both tumor initiation and the development of therapeutic resistance. Accordingly, PDAC cells engage diverse epigenetic, metabolic, and microenvironmental adaptations to evade ferroptotic cell death, thereby sustaining resistance to therapy. Finally, we review the rapidly expanding spectrum of ferroptosis-based therapeutic strategies, encompassing small-molecule inducers, natural products, and, in particular, advanced nanomedicine platforms designed to enhance intratumoral drug delivery, overcome stromal barriers, and enable coordinated induction of ferroptosis while remodeling the tumor microenvironment.