Background:Acute necrotizing pancreatitis is a serious pancreatic injury with limited
effective treatments. This study aims to investigate the therapeutic effects of hesperidin on Larginine-
induced acute pancreatitis and its potential targets.Methods:The authors induced acute pancreatitis in mice by administering two hourly intraperitoneal
injections of L-arginine-HCl, and evaluated the impact of hesperidin on pancreatic and lung
tissues, plasma amylase activity, and myeloperoxidase content. Additionally, necrosis and mitochondrial
function was tested in primary pancreatic acinar cells. The interactions between hesperidin
and proteins involved in necrosis and mitochondrial dysfunction were further invested using in
silico molecular docking and molecular dynamic simulations.Results:Hesperidin effectively ameliorated the severity of acute necrotizing pancreatitis by reducing
plasma amylase, pancreatic MPO, serum IL-6 levels, pancreatic edema, inflammation, and
pancreatic necrosis. Hesperidin also protected against acute pancreatitis-associated lung injury and
prevented acinar cell necrosis, mitochondrial membrane potential loss, and ATP depletion. In addition,
hesperidin exhibited a high binding affinity with SIRT1 and increased the protein levels of
SIRT1. The SIRT1 inhibitor EX527 abolished the protective effect of hesperidin against necrosis
in acinar cells.Conclusion:These findings indicate that hesperidin alleviates the severity of acute necrotizing
pancreatitis by activating SIRT1, which may provide insight into the mechanisms of natural compounds
in treating AP. Hesperidin has potential as a therapeutic agent for acute necrotizing pancreatitis
and provides a new approach for novel therapeutic strategies.