Eriodictyol From Scutellariae Barbata Alleviates Inflammation and Necrosis via ZBP1-dependent Signaling in Acute Pancreatitis

Background Acute pancreatitis (AP) is an inflammatory disease of the pancreas marked by inflammation and acinar cell necrosis. Scutellariae Barbata (S. Barbata), a traditional Chinese herb for inflammation, has unclear efficacy for AP. Purpose This study examined the mechanism of eriodictyol, an active component of S. Barbata decoction, targeting pancreatic necrosis and inflammation for the first time. Study Design This study firstly evaluated the pharmacological effects of S. Barbata on AP. Transcriptomic analysis and pharmacological screening were performed to identify essential genes linked to pancreatic necrosis and specific bioactive compounds in S. Barbata. These candidates underwent thorough validation with multiple assays. Our findings strongly demonstrate effectiveness of S. Barbata in combating pancreatic necrosis and reveal the underlying mechanisms involved. Methods Animal experiments were conducted to assess the effects of S. Barbata on AP. Analysis of bulk and single-cell RNA-seq data identified PANoptosis. The protein-protein interaction network and Cytoscape were used to identify AP targets based on PANoptosis. The ConnectivityMap database was used to filter potential compounds from S. Barbatae based on specific targets. After quantifying eriodictyol, its binding to ZBP1 was confirmed through molecular docking, dynamic simulation, cellular thermal shift assay, mtDNA analysis, and ZBP1 overexpression in 266-6 cells. Experiments in vivo and in vitro assessed the effects of eriodictyol on AP. Results S. Barbata decoction reduced pancreatic inflammation and necrosis. Gene Set Enrichment Analysis of PANoptosis revealed that Zbp1, Nlpr3, Ripk1, Casp8, Gsdmd , and Mlkl are ZBP1-dependent targets for AP. Eriodictyol, the active compound in S. Barbata showed a strong affinity for ZBP1. Eriodictyol may enhance pancreatic conditions and reduce ZBP1-dependent protein expression, with minimal impact on mtDNA levels. Conclusion This study broadened the traditional use of S. Barbata suggested eriodictyol as a potential AP treatment candidate via ZBP1-dependent signaling.