biostudies-literatureAntonucci LNCI NIH HHS1263-1282https://www.ebi.ac.uk/biostudies/studies/S-EPMC12331375biostudies-literatureUnknown6(7)Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H₂O₂ induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor,Nature cancerSelf-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.PMC12331375P01 CA281819U01 CA274295Rundberg Nilsson AEibl GNandi SPMoscat JHu YWaugh TKrawczyk MTsuda MTamayo PSanchez-Lopez EDawson DWBar-Sagi DZhao YGlass CKPuri PLLiu YHatzivassiliou GRoose-Girma MShah VMGu LCaputo LCobo IWu YLowy AMAlexandrov LBRiahi IXu QZhu FSkowronska-Krawczyk DDuran ALi NScott DANicoletti CDiaz-Meco MTMorgan TTodoric JWatari KXian HSears RCAntonucci LVucic EAKarin MfalseSelf-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H₂O₂ induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor,2025-01-01T00:00:00Z2025 Jul2026-04-13T08:17:40.306Z2026-04-07T13:29:35.016ZS-EPMC123313754058852310.1038/s43018-025-01003-3