Mechanism of 6-Gingerol against Cutaneous Squamous Cell Carcinoma Based on Network Pharmacology, Molecular Docking, and In Vitro Validation
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Abstract
Introduction: Cutaneous squamous cell carcinoma (cSCC) is a prevalent non-melanoma skin cancer with increasing global morbidity. Conventional therapies are limited by high recurrence rates and adverse reactions, creating an urgent demand for innovative therapeutic agents. 6-Gingerol, the primary bioactive constituent of ginger, exhibits broad antitumor activity across multiple malignancies, yet its functional mechanism against cSCC remains poorly defined. The study aimed to predict potential molecular mechanisms underlying the anti‑cSCC activity of 6‑gingerol via network pharmacology, molecular docking, and preliminary in‑vitro morphological assays.
Methods: Compound targets of 6-gingerol and disease-related targets of cSCC were retrieved from multiple databases. Intersected targets were applied to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to predict functional biological processes and key signaling cascades. Molecular docking was performed to assess binding affinity between 6-gingerol and hub targets. Hematoxylin-eosin (HE) staining was used to observe morphological alterations in A431 human cSCC cells.
Results: Sixty-one overlapping targets were screened. The PPI network consisted of 61 nodes and 1173 edges, with TP53, AKT1, BCL2, CASP3, and EGFR identified as core hub genes. A total of 522 enriched GO biological processes were obtained, while KEGG enrichment highlighted apoptosis, PI3K-Akt and MAPK signaling pathways. Molecular docking verified strong binding capacity between 6-gingerol and core targets (binding energy ≤ −7.0 kcal/mol). In vitro staining revealed that 6‑gingerol induced morphological changes reminiscent of apoptosis‑like phenotypes in A431 cells. Network pharmacology and molecular docking analyses predicted that 6-gingerol may exert anti-cSCC effects through the regulation of TP53, AKT1, BCL2, and the PI3K-Akt/MAPK pathways.
Conclusion: HE staining provided preliminary morphological evidence of apoptosis-like changes in A431 cells, but the predicted pathway interactions require further experimental validation at the protein and gene expression levels.
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