Quercetin selectively targets gingival squamous cell carcinoma through apoptosis induction, autophagy suppression,...

Oral squamous cell carcinoma (OSCC) remains a major clinical challenge due to high recurrence rates, chemotherapy resistance, and severe treatment-related toxicity. Although quercetin, a naturally occurring flavonoid, has demonstrated anti-cancer properties, its selective activity and molecular mechanisms in distinct OSCC subtypes remain insufficiently characterized.

In this study, we investigated the anti-tumor effects of quercetin in human gingival squamous cell carcinoma (Ca9-22), tongue carcinoma (SCC-9 and CAL-27), and non-malignant oral epithelial (GMSM-K) cells.

Quercetin (0-100 µM) selectively reduced the viability, proliferation, and clonogenic potential of gingival carcinoma cells while exerting limited cytotoxicity toward non-malignant oral epithelial cells, suggesting a favorable therapeutic index. Mechanistically, quercetin induced apoptosis through modulation of intrinsic and extrinsic apoptotic pathways, suppressed autophagy, reduced oxidative stress, promoted DNA damage, and inhibited migratory and metastatic potential. Transcriptomic profiling identified several apoptosis-related genes modulated by quercetin, including CASP9 and BIRC3, whose elevated expression was associated with improved overall survival in head and neck squamous cell carcinoma datasets. In addition, quercetin enhanced the anti-proliferative effects of cisplatin and 5-fluorouracil, supporting its potential role as a chemosensitizing agent in OSCC therapy. Molecular docking and molecular dynamics simulations further demonstrated stable interactions between quercetin and apoptosis- and DNA damage-related proteins, including CASP9, H2AX, and BIRC3.

Collectively, these findings identify quercetin as a selective multi-target anti-cancer compound capable of modulating apoptosis, autophagy, oxidative stress, DNA damage, and metastatic pathways in gingival squamous cell carcinoma. These data support the translational potential of quercetin as a complementary strategy to enhance chemotherapy efficacy in oral cancer.