Abstract: Objective To address the limitations of traditional severe acute pancreatitis (SAP) models and establish a simple, stable, and reliable animal model to enhance the understanding of SAP pathogenesis and facilitate the discovery of therapeutic targets.Methods C57BL/6 mice were pretreated with caerulein followed by pancreatic duct ligation to establish the SAP model. A sham surgery control group was also set up to assess the model's effectiveness. The molecular characteristics and organ damage of the model were evaluated by transcriptomics, immunohistochemistry, and Western blot.Results Mice in the model group exhibited typical SAP pathological features, including elevated serum amylase levels, pancreatic inflammation, and damage to distant organs. Transcriptomic analysis revealed gene expression changes associated with key pathological processes of SAP, validating the scientific value of the model.Conclusions The proposed SAP model is easy to operate, highly reproducible, and provides an efficient tool for investigating the molecular mechanisms of SAP. By revealing potential therapeutic targets, it lays a solid foundation for the development of treatment strategies and the improvement of prognosis for this disease.