Unraveling the therapeutic mechanisms of cinnamaldehyde in allergic rhinitis: a network Pharmacology and experimental approach.

Cinnamaldehyde (CA), a bioactive compound with demonstrated anti-inflammatory and anti-oxidant properties, has been shown to ameliorate allergic rhinitis (AR) pathology. However, its precise mechanisms of action, particularly regarding modulation of ferroptosis and oxidative stress pathways, require further elucidation. Bioinformatics approaches were employed to predict putative targets of CA in AR. Network pharmacology analyses, incorporating protein-protein interaction (PPI) networks, hub gene identification, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, elucidated molecular interactions between CA and AR-associated targets. The functions of CA in interleukin-13 (IL-13)-stimulated human nasal epithelial cells (HNECs) were determined by testing cell viability, lactate dehydrogenase (LDH) activity, inflammatory response, apoptosis, oxidative stress, and ferroptosis. Bioinformatic analysis identified 423 potential targets of CA and 6,712 potential AR-related targets, with 285 shared proteins forming an intricate PPI network. These overlapping targets were significantly associated with key pathways including apoptosis, ferroptosis, tumor necrosis factor (TNF) signaling, and Toll-like receptor pathway. CA mitigated IL-13-evoked inflammatory response, apoptosis, oxidative stress, and ferroptosis in HNECs. Mechanistically, CA decreased toll-like receptor 4 (TLR4) expression in IL-13-stimulated HNECs. Increased TLR4 expression reversed the effects of CA on cell inflammation, apoptosis, oxidative stress, and ferroptosis in IL-13-stimulated HNECs. Our study demonstrates for the first time that CA protects against IL-13-induced cellular damage in HNECs by suppressing oxidative stress, apoptosis, ferroptosis, and inflammatory responses through the downregulation of TLR4.