半枝莲中的圣草酚通过ZBP1依赖性信号通路减轻急性胰腺炎中的炎症和坏死。

Eriodictyol from Scutellariae Barbata alleviates inflammation and necrosis via ZBP1-dependent signaling in acute pancreatitis.

作者信息

Tian Simin, Xin Guang, Zhang Kun, Wen Ao, Yu Xiuxian, Ni Chengyang, Liu Yijiang, Li Xiaojuan, Cao Yu, Huang Wen

机构信息

West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue-Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.

Department of Emergency Medicine, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.

出版信息

Phytomedicine. 2025 May 30;145:156926. doi: 10.1016/j.phymed.2025.156926.

DOI:10.1016/j.phymed.2025.156926

PMID:40544733

Abstract

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 molecular simulation, cellular thermal shift assay, drug affinity responsive target stability, 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.

摘要

背景

急性胰腺炎（AP）是一种以炎症和腺泡细胞坏死为特征的胰腺炎症性疾病。半枝莲，一种用于治疗炎症的传统中草药，对AP的疗效尚不明确。

目的

本研究首次探讨了半枝莲水煎剂的活性成分圣草酚靶向胰腺坏死和炎症的机制。

研究设计

本研究首先评估了半枝莲对AP的药理作用。进行转录组分析和药理筛选，以确定与胰腺坏死相关的关键基因和半枝莲中的特定生物活性化合物。这些候选物通过多种试验进行了全面验证。我们的研究结果有力地证明了半枝莲在对抗胰腺坏死方面的有效性，并揭示了其中的潜在机制。

方法

进行动物实验以评估半枝莲对AP的影响。对批量和单细胞RNA测序数据的分析确定了PANoptosis。蛋白质-蛋白质相互作用网络和Cytoscape用于基于PANoptosis鉴定AP靶点。ConnectivityMap数据库用于根据特定靶点从半枝莲中筛选潜在化合物。在定量圣草酚后，通过分子对接、动态分子模拟、细胞热位移分析、药物亲和力响应靶点稳定性、线粒体DNA分析以及在266-6细胞中过表达ZBP1来确认其与ZBP1的结合。体内和体外实验评估了圣草酚对AP的影响。

结果

半枝莲水煎剂减轻了胰腺炎症和坏死。PANoptosis的基因集富集分析表明，Zbp1、Nlpr3、Ripk1、Casp8、Gsdmd和Mlkl是AP的ZBP1依赖性靶点。半枝莲中的活性化合物圣草酚对ZBP1表现出强烈的亲和力。圣草酚可能改善胰腺状况并降低ZBP1依赖性蛋白表达，对线粒体DNA水平影响最小。