Hypoxia-activated HSP90AA1/STUB1 axis promotes acute pancreatitis via necroptosis protein stabilization

Acute pancreatitis (AP) is a prevalent inflammatory disorder with high mortality in severe cases. Although necroptosis-driven inflammatory cascades significantly contribute to poor prognosis, effective therapeutic interventions remain limited. Here, we investigated the role of necroptosis in AP progression using bioinformatics analysis, co-immunoprecipitation, and ubiquitination assays, alongside in vitro and in vivo cerulein-induced AP models. We demonstrated that the hypoxic microenvironment characteristic of AP activates the HSP90AA1/STUB1 axis through HIF-1α-mediated transcriptional upregulation. The HSP90AA1/STUB1 axis subsequently stabilizes necroptosis executors RIPK1, RIPK3, and MLKL by preventing their ubiquitin-mediated degradation, thereby promoting necroptosis-driven AP progression. This work establishes the hypoxic microenvironment-HIF-1α-HSP90AA1/STUB1-necroptosis axis as a central pathway in AP pathogenesis, revealing novel therapeutic opportunities for targeting necroptosis-driven inflammation in AP.