Pingping Liu,1 Linna Zeng,2 Hongyun Fu,3 Fuzhu Li4 

1Emergency Medicine Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421000, People’s Republic of China; 2Department of Endocrinology, The Third People’s Hospital of Yongzhou, Yongzhou, Hunan, 425000, People’s Republic of China; 3Department of Laboratory Medicine, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421000, People’s Republic of China; 4Department of Neurosurgery Intensive Care Unit, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421000, People’s Republic of China

Correspondence: Fuzhu Li, Department of Neurosurgery Intensive Care Unit, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421000, People’s Republic of China, Tel +86 15773435682, Email lifuzhu1987@163.com

Background: Sepsis is a critical condition characterized by an atypical immune response to infection, resulting in systemic inflammatory response syndrome. Honeysuckle, a traditional Chinese medicinal plant with anti-inflammatory, anti-tumor, and antioxidant characteristics, shows promise in mitigating sepsis-related inflammatory responses. The precise mechanism by which honeysuckle confers protection against sepsis remains uncertain. This research utilized network pharmacology to explore the mechanisms through which honeysuckle mitigates sepsis.
Methods: Bioactive compounds of honeysuckle were sourced from the Traditional Chinese Medicine System Pharmacology database, and their corresponding targets were identified. Sepsis-associated genes were gathered from the GeneCards and Online Mendelian Inheritance in Man databases. The regulatory network depicting “active ingredients-target” relationships was constructed utilizing Cytoscape 3.9.1 software. Target genes affected by honeysuckle in sepsis were analyzed utilizing the String database to create a protein-protein interaction network. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were performed through the Database for Annotation, Visualization, and Integrated Discovery platform, aiming to identify pathways associated with these pivotal targets. Subsequently, molecular docking confirmed the binding capacity of these bioactive ingredients to pivotal targets. Subsequent in vitro experiments were conducted for additional validation. Network pharmacology analysis employed R software for extensive data processing. A Student’s T-test compared the mean values of the two groups in the in vitro experimental data. Statistical analysis for multiple group comparisons was carried out utilizing one-way ANOVA, with Tukey’s post hoc test applied for further analysis.
Results: The screening process identified 23 active ingredients in honeysuckle, which are linked to 291 targets. Molecular docking demonstrated strong binding affinities of kaempferol, luteolin, and quercetin to the target proteins TP53, TLR4, and MYD88. In vitro experiments demonstrated that honeysuckle and its active components mitigate sepsis by inhibiting the TLR4/MYD88 signaling pathways, thereby reducing proinflammatory cytokine production.
Conclusion: These findings indicate that honeysuckle may be an effective treatment for sepsis by modulating key proteins such as TP53, TLR4, and MYD88.

Keywords: network pharmacology, sepsis, molecular docking, traditional Chinese medicine, inflammatory response syndrome