Hyperuricemia aggravates acute pancreatitis through CNR1-mediated inflammatory signaling and gut-pancreas axis dysregulation: a multi-omics and clinical study.

Hyperuricemia (HUA) is implicated in various metabolic and inflammatory diseases. Its role in the pathogenesis of acute pancreatitis (AP), particularly in gut-pancreas crosstalk and the underlying molecular mechanisms, remains poorly understood. This study integrates clinical epidemiology (UK Biobank cohort and the Third Xiangya Hospital cohort), (L-arginine-induced AP mouse models), and multi-omics analyses (RNA sequencing, fecal metabolomics, and gut microbiome profiling) to elucidate the role and mechanistic pathways of uric acid in the onset and severity of AP. Key molecular targets and regulatory relationships identified were further validated via in vitro cellular experiments using pancreatic acinar cells and bone marrow-derived macrophages. In the UK Biobank cohort, over a median follow-up period of 13.69 years, participants in the highest uric acid quartile exhibited a significantly increased risk of developing AP compared to the lowest quartile (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.10-1.43). In the Third Xiangya Hospital cohort, AP patients with elevated serum uric acid levels exhibited more severe symptoms. The combination of uric acid and calcium demonstrated superior predictive capability for AP severity (AUC 0.9504). In the preclinical models, HUA aggravated AP progression, as demonstrated by increased pancreatic histopathological damage, elevated serum amylase levels, multi-organ dysfunction, and higher mortality. Mechanistically, HUA exacerbated AP in mice via cannabinoid receptor 1 (CNR1)-mediated retrograde endocannabinoid signaling, which enhanced macrophage-derived IL-1β and IL-6 production. Metabolomics revealed that the gut-derived flavonoid maesopsin exerted a protective anti-inflammatory effect in the context of HUA-augmented AP. Additionally, Limosilactobacillus genus, particularly Limosilactobacillus reuteri D, was enriched in the HUA + AP group and strongly associated with maesopsin levels. Uric acid exacerbates AP progression via CNR1 driven inflammatory signaling and modulates gut microbiota composition and metabolism. Serum uric acid, especially when combined with calcium, may be integrated into routine clinical assessment for AP risk stratification and severity prediction, while CNR1 and gut microbiota-related targets provided potential directions for the developing adjunctive therapies for HUA-associated AP.