%0 Journal Article
%T IDH2-NADPH pathway protects against acute pancreatitis via suppressing acinar cell ferroptosis.
%A Peng Q
%A Li B
%A Song P
%A Wang R
%A Jiang J
%A Jin X
%A Shen J
%A Bao J
%A Ni J
%A Han X
%A Hu G
%J Br J Pharmacol
%V 0
%N 0
%D 2024 Jul 27
%M 39072736
%F 9.473
%R 10.1111/bph.16469
%X <B>OBJECTIVE: </B>Acute pancreatitis (AP) is associated with acinar cell death and inflammatory responses. Ferroptosis is characterized by an overwhelming lipid peroxidation downstream of metabolic dysfunction, in which NADPH-related redox systems have been recognized as the mainstay in ferroptosis control. Nevertheless, it remains unknown how ferroptosis is regulated in AP and whether we can target it to restrict AP development.<BR><B>METHODS: </B>Metabolomics were applied to explore changes in metabolic pathways in pancreatic acinar cells (PACs) in AP. Using wild-type and Ptf1aCreERT2/+IDH2fl/fl mice, AP was induced by caerulein and sodium taurocholate (NaT). IDH2 overexpressing adenovirus was constructed for infection of PACs. Mice or PACs were pretreated with inhibitors of FSP1 or glutathione reductase. Pancreatitis severity, acinar cell injury, mitochondrial morphological changes and pancreatic lipid peroxidation were analysed.<BR><B>RESULTS: </B>Unsaturated fatty acid biosynthesis and the tricarboxylic acid cycle pathways were significantly altered in PACs during AP. Inhibition of ferroptosis reduced mitochondrial damage, lipid peroxidation and the severity of AP. During AP, the NADPH abundance and IDH2 expression were decreased. Acinar cell-specific deletion of IDH2 exacerbated acinar cell ferroptosis and pancreatic injury. Pharmacological inhibition of NADPH-dependent GSH/GPX4 and FSP1/CoQ10 pathways abolished the protective effect of IDH2 overexpression on ferroptosis in acinar cells. CoQ10 supplementation attenuated experimental pancreatitis via inhibiting acinar cell ferroptosis.<BR><B>CONCLUSIONS: </B>We identified the IDH2-NADPH pathway as a novel regulator in protecting against AP via restricting acinar cell ferroptosis. Targeting the pathway and its downstream may shed light on AP treatment.