NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions
Recommended Citation
Radyk MD, Nelson BS, Ruckert MT, Halbrook CJ, Shan M, Alektiar JM, Lavoie BL, Salvatore L, Yan W, Perricone MD, Buscher K, Wood A, Hong HS, Sajjakulnukit P, Zhang L, Corfas G, Bednar F, Frankel TL, Pasca di Magliano M, Colacino JA, Shah YM, Crawford HC, Lyssiotis CA. NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions. Nat Metab. 2026;8(4):824-839.
Document Type
Article
Publication Date
4-1-2026
Publication Title
Nat Metab
Keywords
Animals, Mice, Precancerous Conditions, Pancreatic Neoplasms, NADP, Humans, Glucosephosphate Dehydrogenase, Oxidative Stress, Carcinoma, Pancreatic Ductal, Reactive Oxygen Species, Metaplasia, NF-E2-Related Factor 2, Malate Dehydrogenase
Abstract
Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.
Medical Subject Headings
Animals; Mice; Precancerous Conditions; Pancreatic Neoplasms; NADP; Humans; Glucosephosphate Dehydrogenase; Oxidative Stress; Carcinoma, Pancreatic Ductal; Reactive Oxygen Species; Metaplasia; NF-E2-Related Factor 2; Malate Dehydrogenase
PubMed ID
41922743
ePublication
ePub ahead of print
Volume
8
Issue
4
First Page
824
Last Page
839
