Assessing the rosacea potential pathogenic risks of cinnamaldehyde in daily skin care products and cosmetics using network toxicology and molecular docking with experimental validation

Rosacea, a chronic inflammatory skin disorder, severely impairs patients’ quality of life and imposes substantial medical burdens. Existing treatments are hampered by unsatisfactory therapeutic effects and high recurrence rates, driving urgent research into novel pathogenic mechanisms. As a common spice and cosmetic preservative, cinnamaldehyde’s safety risks in rosacea patients remain poorly characterized. This study aimed to integrate network toxicology with in vitro cellular assays to clarify its pathogenic roles and molecular pathways, providing novel theoretical support for its adverse impacts on rosacea sufferers. First, we predicted the target genes of cinnamaldehyde using the PubChem, SwissTargetPrediction, SuperPred, and ChEMBL databases. Second, we obtained relevant targets for rosacea using the GeneCards and CTD databases and identified the intersection targets with toxic substances. Then, we constructed a protein–protein interaction network of the core toxic substance combination using the STRING database and performed Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis to predict possible mechanisms. Subsequently, molecular docking validation of the active ingredients with the main targets was performed using AutoDock Vina software. Finally, cinnamaldehyde was added to the rosacea-like cellular model in HaCaT cells to assess its effects and molecular mechanisms by Cell Counting Kit-8, reverse transcription quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. Database screening revealed 43 overlapping targets between the 195 predicted targets of cinnamaldehyde and the 1889 disease-related targets for rosacea, which included notable proteins such as prostaglandin‑endoperoxide synthase 2 (cyclooxygenase‑2; PTGS2), matrix metallopeptidase 9 (MMP9), and epidermal growth factor receptor (EGFR). Protein–protein interaction analysis identified PTGS2 as a pivotal hub protein, while Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that interleukin-17 signaling and lipid metabolism are vital mechanisms involved in rosacea. Molecular docking studies demonstrated strong binding affinities between cinnamaldehyde and the identified core targets. Furthermore, cell culture experiments confirmed that cinnamaldehyde exacerbates rosacea by upregulating the expression of PTGS2, MMP9, and EGFR, along with increasing the production of inflammatory cytokines such as interleukin-8 and interleukin-1 beta. In summary, our findings elucidate the potential pathogenic mechanisms by which cinnamaldehyde may induce rosacea, highlighting the roles of the core targets PTGS2, MMP9, and EGFR in mediating inflammation. This research provides new scientific insights that could inform preventive strategies and therapeutic interventions aimed at managing the toxicity associated with rosacea.