ORM2 protects against acute pancreatitis by inhibiting premature activation of pancreatic enzymes.

BACKGROUND: Acute pancreatitis (AP) is characterized by dysregulated pancreatic enzyme activation and pancreatic tissue injury. Orosomucoid (ORM), an acute-phase protein with immunomodulatory functions, exhibits organ-specific expression patterns, but its role in AP remains unclear. This study investigated the isoform-specific effects of ORM2 in AP pathogenesis and repair. METHODS: We established cerulein-induced mouse model of AP using both wild-type and pancreas-specific ORM2 knockout mice to investigate ORM2's protective role. Primary acinar cells were used for in vitro validation. Proteomics and functional assays elucidated mechanisms. RESULTS: In AP models, we observed opposing expression patterns of ORM, with increased levels in the liver but decreased levels in the pancreas. Genetic deletion of pancreatic ORM2 significantly worsened AP severity, while exogenous ORM2 administration provided protection against pancreatic injury. Specifically, ORM2 upregulated SPINK1 while downregulating PRSS2, leading to reduced trypsin activation. CONCLUSIONS: ORM2 protects against AP by modulating the SPINK1-PRSS2 axis to prevent premature trypsin activation and alleviate acinar cell injury. Its tissue-specific regulation suggests therapeutic potential for AP.