ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas
Year: 2026
Type: article
Abstract: 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.
Source: Nature Metabolism
Authors: Marc Hennequart, Loic Mervant, Julie Stockis, Jack Coomes, Martha M. Zarou, Louise Gerard, Virginie Tevel, Valérie Migeot, Steven E. Pilley, Younghwan Lee, Paul C. Driscoll, Nathalie M. Legrave, Christiaan F. Labuschagne, Fabio Zani, Alejandro Huerta Uribe, Rute Machado De Morais Ferreira, Eric C. Cheung, Ilaria Malanchi, James I. MacRae, Oliver D. K. Maddocks, Timotheus Y. F. Halim, Karen H. Vousden
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7147168275