The role and regulatory mechanism of USP25 in pancreatic microcirculatory disturbance in severe acute pancreatitis

This study investigates the molecular mechanism by which USP25 contributes to pancreatic microcirculatory disturbance in severe acute pancreatitis (SAP). SAP was induced by retrograde injection of 4% sodium taurocholate into the pancreatic duct following adenoviral delivery of sh-USP25 to suppress USP25 expression. Renin activity, and serum concentration of angiotensin II, endothelin, and NO were recorded. Pancreatic histopathology was assessed via H&E staining. Microcirculatory disturbance was evaluated after FITC-RBC infusion by measuring red blood cell flow rate, flow velocity, and functional vessel count. An in vitro SAP model was established by treating rat pancreatic acinar cell AR42J with cerulein. USP25 and TRAF6 expression levels in tissues and cells were examined using qRT-PCR and Western blotting. Cell viability and death were assessed using the CCK-8 assay and Hoechst33342/PI staining respectively. Co-immunoprecipitation confirmed the interaction between USP25 and TRAF6. TRAF6 ubiquitination was quantified following MG132 treatment. USP25 was markedly upregulated in pancreatic tissues of SAP rats. USP25 inhibition alleviated pancreatic microcirculatory disturbance and ameliorated pancreatic injury. USP25 directly bound to TRAF6 and stabilized its protein level by reducing TRAF6 ubiquitination. In conclusion, USP25 promotes pancreatic microcirculatory disturbance in SAP by stabilizing TRAF6 through deubiquitination, revealing a critical USP25-TRAF6 regulatory axis that drives SAP progression.