E3 ubiquitin ligase Pellino1 suppresses acinar cell necroptosis and alleviates severe acute pancreatitis by promoting ubiquitin‐dependent receptor‐interacting protein kinase 3 (RIP3) degradation

BACKGROUND AND PURPOSE: Severe acute pancreatitis (SAP) is a critical abdominal condition with high mortality rates. The activation of necroptosis in acinar cells is an critical mechanism for SAP. Pellino1 (PELI1), as an E3 ubiquitin ligase, is involved in pathogenic mechanisms in various diseases. Its ubiquitination function also can regulate necroptosis. However, in SAP, there is a lack of research on upstream regulatory mechanisms and small molecule-targeted drug therapy of necroptosis. Therefore, it is of great significance to study the specific mechanism of PELI1 regulating necroptosis in SAP. EXPERIMENTAL APPROACH: We designed animals and cells with overexpression and knockdown of PELI1 to study the role of PELI1 in SAP, detect the ubiquitination regulatory mechanism of PELI1 on necroptosis and explore the therapeutic effect of GSK-872 in SAP models in vitro and in vivo. KEY RESULTS: We revealed that PELI1 expression was significantly down-regulated in SAP mouse models and in vitro SAP cell models. Additionally, the overexpression experiments at the cellular and animal levels confirmed the protective effect of PELI1 in SAP and its negative regulatory effect on necroptosis. Mechanistically, our investigation identified that PELI1 degraded RIP3 through K48-linked ubiquitination to inhibit necroptosis, and thereby promote acinar cell activity. Furthermore, we found that GSK-872 effectively inhibited necroptosis and alleviated pancreatic damage in SAP. CONCLUSIONS AND IMPLICATIONS: Our findings highlight the protective role of PELI1-mediated ubiquitination-dependent proteasomal degradation of RIP3 in SAP and propose pharmacological inhibition of RIP3 as a promising strategy to combat SAP.