Background <p>Acute pancreatitis (AP) can progress to severe acute pancreatitis (SAP), which is characterized by systemic inflammatory response syndrome (SIRS), and SAP patients generally have a poor prognosis and high mortality. Therefore, early assessment of disease severity and timely intervention are crucial for reducing inflammation and mortality in AP patients. Our previous research found that membrane-associated RING-CH E3 ubiquitin ligase 9 (MARCH9) inhibits the production of reactive oxygen species (ROS) and the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome by mediating the ubiquitination and degradation of NADPH oxidase 2 (NOX2), thereby alleviating NLRP3-mediated acinar cell injury in rats. In this study, we investigated the correlation between the expression of MARCH9 in peripheral blood mononuclear cells (PBMCs) from AP patients and the disease severity, expression of NLRP3 inflammasome, and the associated inflammatory cytokines.</p> Methods <p>This study included 85 patients with AP who were admitted within 48&#xa0;h of onset, including 40 patients with mild acute pancreatitis (mild acute pancreatitis, MAP) and 45 patients with non-mild acute pancreatitis (non-mild acute pancreatitis, Non-MAP). Additionally, 30 healthy volunteers were enrolled as the control group, and PBMCs and serum samples were collected from all participants. The basic clinical characteristics of all patients were thoroughly recorded and analyzed. The mRNA and protein expression levels of MARCH9, NLRP3, interleukin-1β (IL-1β), caspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC) in PBMC samples were assessed using real-time reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The levels of IL-1β and interleukin-18 (IL-18) in serum samples were measured using enzyme-linked immunosorbent assay (ELISA). To identify the most clinically significant features, the least absolute shrinkage and selection operator (Lasso) regression analysis with L1 regularization was used for feature selection. The sensitivity, specificity, and clinical decision-making value of the model were evaluated by plotting the receiver operating characteristic curve (ROC) and performing decision curve analysis (DCA).</p> Results <p>In non-MAP patients, white blood cell count, platelet count, and procalcitonin levels were significantly higher than in MAP patients. Additionally, non-MAP patients exhibited significantly elevated scores in the acute physiology and chronic health evaluation (APACHE II), bedside index for severity in acute pancreatitis (BISAP), and modified CT severity index (MCTSI). Correlation analysis revealed that the expression level of MARCH9 in PBMC was negatively correlated with disease severity, the expression of the NLRP3 inflammasome, and the expression of its derived inflammatory cytokines. The ROC analysis indicated that the AUC of MARCH9 mRNA was 0.868 (95% CI: 0.788–0.947), with its predictive performance comparable to that of the BISAP score (AUC = 0.883), and significantly superior to traditional inflammatory markers (IL-1β, IL-18). Further analysis using DCA confirmed that the combination of MARCH9 and the BISAP score significantly improved the clinical decision-making net benefit (threshold probability &gt; 20%).</p> Conclusion <p>MARCH9 could serve as a novel biomarker for the diagnosis and severity assessment of AP, and is negatively correlated with the expression of the NLRP3 inflammasome and its downstream inflammatory cytokines in AP patients.</p>