Dual Role of NRF2 in Shaping Pancreatic Premalignant Tumors

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal cancers, with survival rates stubbornly low despite advances in treatment. Intraductal papillary mucinous neoplasm (IPMN) emerges as a distinct premalignant pathway, separate from the more commonly studied pancreatic intraepithelial neoplasia (PanIN). The ability to detect IPMN through imaging before malignant progression offers a transformative opportunity for early intervention in pancreatic cancer. However, the molecular determinants driving the formation of different premalignant lesions remain incompletely understood. Our study uncovers a previously unrecognized role for NRF2, a master regulator of redox homeostasis, in shaping the fate of pancreatic precursors. While NRF2 is known to promote PanIN formation and sustain PDA, we discovered a striking decrease in active NRF2 levels in human IPMN compared to PanIN and PDA. Using a conditional NRF2 knockout mouse model, we further demonstrate that NRF2 loss significantly increases the development of IPMN-like cystic tumors in KRASG12D-mutant pancreatic epithelium, revealing an unexpected role of NRF2 in suppressing IPMN. Intriguingly, while NRF2 promotes PanIN formation through redox-dependent mechanisms, its suppression of IPMN operates via a distinct pathway: the transcriptional repression of SPDEF and MUC6, both key markers of IPMN. These findings illuminate the dual and context-dependent roles of NRF2 in pancreatic tumorigenesis, providing novel insights into the molecular underpinnings of lesion-specific progression in PDA.