Abstract

Abstract Objectives This study investigated the protective effects and mechanisms of rhaponticin (Rha) against acinar cell injury in acute pancreatitis (AP). Methods Pancreatic acinar cell injury was induced using multiple in vitro and in vivo AP models. The mitochondrial function, necrosis, and oxidative stress were assessed. Network pharmacology and molecular docking were applied to predict potential molecular targets, which were subsequently validated experimentally. The involvement of hypoxia-inducible factor 1-alpha (HIF-1α) signaling and necroptosis-related proteins, including receptor-interacting protein kinase 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL), was further explored. Both pharmacological inhibition and siRNA-mediated knockdown were employed to verify the target specificity of Rha. Results Rha treatment significantly preserved mitochondrial function, reduced ROS, and alleviated pancreatic injury. Network pharmacology and molecular dockingresults identified HIF -1a as the key target of Rha. Consistently, Rha treatment markedly downregulated HIF-1α expression and inhibited necroptosis by suppressing the activation of RIP3 and p-MLKL. Notably, neither pharmacological inhibition nor siRNA-mediated knockdown of HIF-1α produced additional protective effects in the presence of Rha, indicating the involvement of HIF-1α in mediating its actions. Conclusion Rha effectively attenuates acinar cell necrosis and oxidative via the HIF-1α-mediated necroptosis pathway, highlighting Rha as a promising therapeutic candidate for AP.