Drosophila -based screening identifies ferroptosis induction via NAD-GPx4 axis inhibition as a therapeutic strategy for PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, and substantial progress has been made using mammalian models to elucidate its pathogenic mechanisms. To enable systematic discovery of actionable vulnerabilities, we generated a Drosophila PDAC model library that recapitulates key genetic alterations observed in human disease. Among these models, the “4-hit” flies-harboring alterations in KRAS , TP53 , CDKN2A , and SMAD4 , a genotype associated with the poorest clinical prognosis-exhibited robust tumorigenic manifestations, including epithelial transformation and impaired organismal viability. A genetic screen using this high-fidelity model uncovered a critical role for the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway in promoting PDAC progression. Within this pathway, we identified glutathione peroxidase 4 (GPx4) as a key effector that mitigates reactive oxygen species (ROS)-mediated cytotoxicity. Combined inhibition of GPx4 and MEK using ML210 and trametinib, respectively, markedly ameliorated lethality and tumor-like phenotypes in the 4-hit flies. Importantly, this combinatorial treatment synergistically suppressed proliferation of human PDAC cells and their corresponding xenografts, primarily by inducing ROS accumulation and triggering ferroptotic cell death.Collectively, these findings reveal a conserved dependency of PDAC on the NAD-GPx4 redox axis and demonstrate that therapeutic induction of ferroptosis represents a promising strategy to target genetically refractory PDAC.