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Acute pancreatitis (AP), known for its rapid onset and significant incidence and mortality rates, presents a clinical challenge due to the limited availability of effective treatments and preventive measures. Anemarsaponin B (ASB) has emerged as a potential therapeutic agent, demonstrating capabilities in reducing immune inflammation, positioning it as a promising candidate for AP treatment. Methods: We investigated the effects of ASB on AP in mice, induced by caerulein and lipopolysaccharide (LPS). Peripheral blood samples were collected 24 h post-induction with caerulein to assess of key biomarkers including lipase, amylase, TNF-a, IL-1ß, IL-6, SOD, and GSH-Px. A range of techniques such as immunohistochemistry staining, immunofluorescence staining, Western blotting, and quantitative Polymerase Chain Reaction (q-PCR), were employed to measure the expression of critical genes. Additionally, pancreas samples from the mice were harvested for microbiome and metabolome sequencing, with the data analyzed to understand the impact of ASB on AP. Results: Our study revealed that, compared to the sham group, the AP group exhibited significantly higher serum levels of lipase, amylase, and cytokines, while levels of SOD and GSH Px were notably lower. Treatment with ASB led to a substantial decrease in the levels of lipase, amylase, and cytokines, and an increase in SOD and GSH-Px levels. q-PCR analysis of pancreatic histiocytes corroborated these serum findings. Hematoxylin and Eosin (H&E) staining indicated significant alterations in the pathological changes in the pancreas, lungs, and small intestine of the AP model due to ASB. Immunofluorescence assays demonstrated that ASB alleviated the apoptosis of pancreatic histiocytes in the AP model. Western Blot and histological analyses showed that ASB reduced the phosphorylation of TAK, p38, JNK, and ERK proteins, as well as the levels of TRAF6 protein in the AP model. Furthermore, metabolomic and gut microbiota analysis identified 27 differential metabolites and 34 differential species. The combined metabolome and microbiome analysis suggested an association between certain microbes (e.g., unclassified-Saprospiraceae and unclassified-Micavibrionales) and metabolites (e.g., LysoPE (0:0/20:0), PC (DiMe(13,5)/PGJ2)), and Heptanoic acid, indicating potential pathways through which ASB may exert its therapeutic effects in AP. Conclusions: ASB exhibits therapeutic efficacy in treating AP induced by caerulein combined with lipopolysaccharide (LPS), primarily through modulating the mitogenactivated protein kinase (MAPK) signaling pathway. This discovery offers fresh perspectives for AP drug development, underscoring the potential of targeting specific cellular pathways. Additionally, the intricate interplay observed between the gut microbiota and metabolites following ASB treatment highlights novel therapeutic targets, suggesting that manipulating the gut microbiome and metabolome could be a viable strategy in AP management. These findings pave the way for further research into comprehensive treatment approaches that incorporate both pharmacological intervention and microbiota modulation. [ABSTRACT FROM AUTHOR]