Elucidating the integrative role and possible molecular mechanisms of Salvia miltiorrhiza ingredients and gut microbiota-derived metabolites in alleviating pyroptosis-mediated hepatic ischemia–reperfusion injury through network pharmacology

Currently, therapeutic options for hepatic ischemia–reperfusion injury (HIRI) remain limited and challenging. An emerging alternative involves the combination of ingredients from traditional Chinese medicine (TCM) and beneficial gut microbiota (GM) metabolites. This study integrates ingredients of Salvia miltiorrhiza (SM) and metabolites of GM to assess their combined therapeutic efficacy against HIRI through pyroptosis using network pharmacology. Twenty-nine final targets were recognized as key proteins responsible for the alleviation of HIRI by SM ingredients and GM metabolites through pyroptosis, with GAPDH, AKT1, ILB1 emerging as central targets in the protein–protein interaction (PPI) network. The Toll-like receptor (TLR), NOD-like receptor (NLR), IL-17, TNF and MAPK signalling pathways were identified as key pathways in the therapeutic effects of SM ingredients and GM metabolites. Eight microRNAs (miRNAs) were predicted to be potential miRNAs exerting the most influence. Four SM ingredients and 11 GM metabolites were identified as non-toxic, promising candidates against HIRI. Moreover, the results of molecular docking showed all compounds were well combined with the corresponding proteins. This study highlights the therapeutic potential of TCM and beneficial GM in HIRI treatment and provides a foundational dataset for future research on their combined application. Further in vitro and in vivo studies are needed to validate these findings.

目前，肝缺血再灌注损伤（hepatic ischemia–reperfusion injury, HIRI）的治疗手段仍较为有限且颇具挑战性。一种新兴的治疗策略为联合应用传统中药（traditional Chinese medicine, TCM）成分与有益肠道菌群（gut microbiota, GM）代谢产物。本研究整合丹参（Salvia miltiorrhiza, SM）成分与肠道菌群代谢产物，通过网络药理学方法评估二者通过调控细胞焦亡（pyroptosis）对抗肝缺血再灌注损伤的联合治疗效果。最终筛选得到29个关键靶点蛋白，它们是丹参成分与肠道菌群代谢产物通过调控细胞焦亡以缓解肝缺血再灌注损伤的核心作用靶点，其中甘油醛-3-磷酸脱氢酶（GAPDH）、AKT1、ILB1为蛋白质相互作用（protein–protein interaction, PPI）网络中的核心靶点。研究识别出Toll样受体（Toll-like receptor, TLR）、NOD样受体（NOD-like receptor, NLR）、IL-17、肿瘤坏死因子（TNF）及丝裂原活化蛋白激酶（MAPK）信号通路为二者联合治疗的关键通路。共预测得到8种微小RNA（microRNAs, miRNAs）为发挥主要调控作用的潜在miRNA。筛选出4种丹参成分与11种肠道菌群代谢产物为无毒且极具开发前景的抗肝缺血再灌注损伤候选物质。此外，分子对接实验结果显示，所有受试化合物均可与对应靶点蛋白形成稳定结合。本研究证实了传统中药与有益肠道菌群联合用于肝缺血再灌注损伤治疗的潜在应用价值，同时为二者联合应用的后续研究提供了基础数据集。未来仍需开展体外与体内实验以验证本研究结论。