Network pharmacology analysis of sleep disorders and Magnolia officinalis

Background: Sleep disorders, encompassing more than 90 subtypes including insomnia, pose significant risks for neurodegenerative and metabolic dysregulation. Current therapies remain limited in multi-pathway modulation. Magnolia officinalis (Houpo), a traditional herb for "regulating Qi and resolving dampness," has demonstrated sleep-promoting effects, yet its network-level mechanisms remain uncharacterized. Methods: An integrated network pharmacology approach was employed. Targets of sleep disorders (n=2298) and Magnolia officinalis (n=198) were retrieved from TCMSP, HERB, and GeneCards. Venn analysis identified 104 overlapping targets. Protein-protein interaction (PPI) networks were constructed via STRING and Cytoscape (v3.10.2) with Maximal Clique Centrality (MCC) algorithm screening for hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Gens and Genomes (KEGG) analyse were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: Ten hub genes were identified, including tumor necrosis factor (TNF), hypoxia-inducible factor 1 alpha (HIF1A), epidermal growth factor receptor (EGFR), cyclin D1 (CCND1), caspase 3 (CASP3), AKT serine/threonine kinase 1 (AKT1), tumor protein p53 (TP53), cytochrome c somatic (CYCS), BCL2 like 1 (BCL2L1), and BCL2 apoptosis regulator (BCL2). GO analysis revealed key involvement in neuronal processes: cyclic nucleotide-coupled GPCR signaling, nicotine response, and synaptic regulation. KEGG analysis demonstrated enrichment in neuroactive ligand-receptor interaction, serotonergic synapse, and apoptosis pathways. Mechanistically, magnolol (primary bioactive) concurrently modulates: (1) GABAergic transmission via CCND1-mediated GABAaR phosphorylation; (2) TNF/CASP3-dependent neuroinflammation; (3) hypoxia adaptation through potential regulation of HIF1α signaling; (4) gut-brain axis via potential involvement of AKT1-related pathways; (5) mitochondrial apoptosis (BCL2/BCL2L1). Conclusions: This study deciphers the multi-target synergy of Magnolia officinalis across neurotransmitter-circadian, inflammatory-metabolic, and apoptotic modules, providing a molecular basis for its traditional use and positioning it as a promising polypharmacological agent against sleep disorders.