Resveratrol synergizes with chloroquine to inhibit the malignant progression of oral squamous cell carcinoma by regulating KIF11.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with limited therapeutic options and poor prognosis. Resveratrol, a natural polyphenol, and chloroquine, an established antimalarial drug, have shown potential anticancer effects individually. However, the rationale for investigating their combined action specifically against OSCC lies in the urgent need for novel, effective treatments and the promise of repurposing existing drugs. This study explored their regulatory mechanism in OSCC. Potential targets of chloroquine and resveratrol were predicted using the SwissTarget database, while OSCC-related targets were identified via the GeneCards database. Key overlapping genes underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking simulation and cellular thermal shift assay were used to assess binding affinity between the compounds and kinesin family member 11 (KIF11). KIF11 mRNA expression was detected by quantitative real-time polymerase chain reaction. Protein expression was detected by western blotting assay or immunohistochemistry assay. Cell viability was analyzed by cell counting kit-8 assay. Cell proliferation was analyzed by 5-Ethynyl-2'-deoxyuridine assay. Cell apoptosis was analyzed by flow cytometry. Cell invasion was analyzed by transwell invasion assay. Cell migration was analyzed by wound-healing assay. Colorimetric assays were used to analyze Fe2+ and iron levels. An in vivo xenograft mouse model was used to evaluate the effects of resveratrol and chloroquine on tumor growth. KIF11 was identified as a common target of both chloroquine and resveratrol in OSCC. Incubation with chloroquine or resveratrol led to a significant thermostability of KIF11 at different temperatures. In addition, KIF11 expression was upregulated in OSCC tissues and cells. The results also showed that silencing KIF11 expression significantly suppressed OSCC cell proliferation, migration, and invasion, while inducing apoptosis and ferroptosis. Crucially, chloroquine and resveratrol acted synergistically. This combination potently inhibited OSCC cell proliferation, migration, and invasion, and promoted apoptosis and ferroptosis through KIF11 regulation. These inhibitory effects on malignant phenotypes by chloroquine and resveratrol were consistently confirmed in vivo using the CAL27 cell xenograft model. Resveratrol synergized with chloroquine to suppress OSCC progression by targeting KIF11, effectively inhibiting proliferation, migration, invasion, and promoting apoptosis and ferroptosis. This study provides a mechanistic basis for the combined use of resveratrol and chloroquine, highlighting KIF11 as a critical therapeutic target.