RIPK3 Promotes Acute Pancreatitis via TRAF6-K63 Ubiquitination and Downstream Signaling Activation

Acute pancreatitis is a condition characterized by the injury and death of pancreatic acinar cells caused by multiple factors, ultimately leading to local or systemic inflammatory responses. Existing treatment methods for acute pancreatitis, especially severe acute pancreatitis, are still limited. Previous studies have shown that RIPK3 makes a prominent contribution to the regulation of pancreatic acinar cell necroptosis. In this study, our research has found that RIPK3 also plays an indispensable role in regulating the inflammatory response of macrophages. Studies have shown that the RIPK3 inhibitor GSK-872 and conditional knockout of RIPK3 in macrophages effectively alleviate pancreatic tissue damage. It is also elucidated that macrophage RIPK3 interacts with TRAF6, facilitates TRAF6-K63 ubiquitination, triggers the activation of the NF-κB and MPAK inflammatory signaling pathways, rather than through the necroptosis mechanism, and promotes the occurrence and development of acute pancreatitis. This study will focus on exploring the regulatory role and mechanism of RIPK3 in macrophages, providing new strategies and targets for the therapy of acute pancreatitis.