ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas
(2026) Nature Metabolism — Vol. 8, n° 4, p. 810-823 (2026)
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- Acinar-to-ductal metaplasia (ADM) contributes to pancreatic repair after injury 1. However, persistent ADM, combined with KRAS mutation, leads to the development of precancerous pancreatic intraepithelial neoplasia (PanIN) that can progress into pancreatic ductal adenocarcinoma (PDAC) 2. While PDAC development is well documented, the metabolic rewiring that occurs during early events such as ADM is poorly understood. Here we show that aldehyde dehydrogenase 1 family member L2 (ALDH1L2), an NADPH-producing mitochondrial enzyme of the one-carbon pathway, limits reactive oxygen species (ROS) and formate production in pancreatic acinar cells. However, ALDH1L2 expression decreases progressively during ADM and is completely absent in pancreatic ductal cells. ALDH1L2 loss elevates ROS and promotes ADM in a model of pancreatitis and accelerates tumour progression in models of pancreatic cancer. We also show that formate increases during PDAC progression in mice and humans. Overall, our findings identify ROS as a driver of ADM and suggest that circulating formate may serve as a biomarker for PDAC progression. The pancreas regulates digestion and controls blood sugar. In the endocrine pancreas, the islets of Langerhans produce hormones such as insulin and glucagon that allow for the tight control of circulating glucose levels 3. The exocrine pancreas, which represents up to 95% of the total pancreatic mass, is composed of acinar and ductal cells. The acinar cells, which constitute the majority of the exocrine pancreas, produce digestive enzymes such as proteases, lipase and amylase. Ductal cells produce an alkaline fluid that prevents aggregation of the digestive enzymes and water 3,4. Pancreatitis, which is characterized by damage and inflammation of the pancreas, can be caused by many factors, including alcohol consumption and gallstones. Acinar cells exhibit plasticity and in response to damage, they de-differentiate and take on some of the characteristics of ductal cells in a process termed acinar-to-ductal metaplasia (ADM) 5,6. This is not a true transdifferentiation event as cells do not gain all the characteristic of ductal cells, rather adopting a progenitor-like phenotype 7. They cease to secrete digestive enzymes and acquire an ability to proliferate that contributes to the regenera-tion of tissue after the damage is resolved. Furthermore, the ADM process can be reversed to re-establish normal pancreatic structure and function 1,7. While acute pancreatitis can resolve over time, chronic pan-creatitis is a known risk factor for pancreatic ductal adenocarcinoma
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Marc Hennequart, Loic Mervant, Stockis, J., Jack Coomes, Martha M Zarou, Gérard, L., Virgine Tevel, Valerie Migeot, Steven E. Pilley, Younghwan Lee, Paul C. Driscoll, Nathalie Legrave, Christiaan F. Labuschagne, Fabio Zani, Alejandro Huerta Uribe, Rute Machado De Morais Ferreira, Eric C. Cheung, Ilaria Malanchi, James I. MacRae, et al. (2026). ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas. Nature Metabolism, 8(4), 810-823. https://doi.org/10.1038/s42255-026-01456-5 (Original work published 2026)