Pharmacological inhibition of frizzled 4 delays cell cycle progression and limits oral squamous cell carcinoma growth.

Oral squamous cell carcinoma is an aggressive malignancy driven by aberrant signaling pathways, with Wnt signaling acting as a central regulator of proliferation, tumor-microenvironment interactions, and oncogenic growth. Here, we focus on Frizzled-4, a Wnt receptor with context-dependent functions in epithelial cancers. We show that pharmacological inhibition of Frizzled-4 delays cell cycle progression, and reduces proliferative capacity. These effects are accompanied by suppressed metabolism of retinoic acid, suggesting that Frizzled-4 inhibition stabilizes intracellular retinoic acid levels, which ultimately contributes to the observed cell cycle slowdown. Blocking retinoic acid signaling reverses the cell cycle effects of Frizzled-4 inhibition, confirming that retinoic acid-dependent regulation operates downstream of Frizzled-4. By restraining uncontrolled proliferation and attenuating oncogenic signaling, Frizzled-4 emerges as a key molecular node in oral squamous cell carcinoma, highlighting its potential as a therapeutic target to counteract Wnt-driven tumor growth.