The molecular network mechanism of linalool in arthritis-related pain alleviation via hypothalamic regulation

Background: This study investigates the molecular mechanisms by which linalool, a plant-derived monoterpene, alleviates arthritis-related pain through hypothalamic regulation using network pharmacology. Methods: Gene targets were retrieved from the GeneCards database by using the keywords “linalool,” “arthritis,” “pain,” and “hypothalamus.” To comprehensively obtain targets of linalool, other databases like Traditional Chinese Medicine Systems Pharmacology (TCMSP), the Encyclopedia of Traditional Chinese Medicine (ETCM), HERB, DrugBank, PubMed, and China National Knowledge Infrastructure (CNKI) were used to get linalool-related targets. Then, we performed Venn analysis to identify the overlapped genes, which were employed for functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed to visualize the gene interaction with certain signaling pathways. Results: Venn analysis identified 16 overlapping genes, among which, IL6, IL1β, CASP3, CASP9, mTOR were five hub genes involved in therapeutic mechanism of linalool in arthritis, pain, and hypothalamus. Enrichment analysis highlighted NF-κB and JAK-STAT signaling pathways as critical mediators of inflammation and pain modulation in the hypothalamus, while PPI network analysis revealed that hub genes were highly correlated with inflammatory and apoptotic pathways. Conclusions: Network pharmacology analysis showed linalool suppressed pro-inflammatory cytokines (IL-6, IL-1β) and apoptotic markers (CASP3, CASP9), while restoring mTOR expression and GABAergic inhibitory tone in the hypothalamus. These findings provide novel insights into hypothalamic pain processing and indicate linalool as a promising multi-target phytotherapy for chronic inflammatory pain.