CA9-related ferroptosis is a potential therapeutic target of kaempferol anti-oral squamous cell carcinoma.

BACKGROUND

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, affecting the tongue, palate, mouth floor, alveolar ridge, and buccal mucosa. Kaempferol, a natural flavonoid, exhibits anti-oral cancer properties, but its mechanisms remain unclear. This study aimed to investigate kaempferol's therapeutic potential and molecular mechanisms in OSCC using network pharmacology, molecular docking, and experimental validation.

METHODS

Kaempferol's components and targets were identified via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). OSCC-related genes were sourced from GeneCards and Gene Expression Omnibus (GEO) databases. Network and molecular docking analyses were performed using Cytoscape and Autodock, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). In vitro and in vivo experiments validated kaempferol's effects.

RESULTS

Kaempferol induced ferroptosis, reducing OSCC cell viability and increasing apoptosis dose-dependently. Carbonic anhydrase IX (CA9) emerged as a core gene mediating kaempferol's anti-OSCC effects via ferroptosis. Molecular docking confirmed strong binding affinity between kaempferol and CA9 (-6.24 kcal/mol). GO and KEGG analyses revealed kaempferol's modulation of p53/FoxO/cellular senescence pathways. Experiments confirmed kaempferol's inhibition of OSCC proliferation and migration through CA9/ferroptosis induction.

CONCLUSIONS

Kaempferol exerts anti-OSCC effects via CA9/ferroptosis, highlighting its potential as a therapeutic agent for OSCC.