ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
This article is part of the Research TopicProgress in Molecular Mechanisms and Targeted Therapies for Solid Tumor MicroenvironmentsView all 14 articles
Pharmacological Inhibition of Frizzled 4 Delays Cell Cycle Progression and Limits Oral Squamous Cell Carcinoma Growth
Provisionally accepted
- University of Zurich, Zürich, Switzerland
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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.
Keywords: FZD4, FzM1, oral squamous cell carcinoma, Retinoic acid, Wnt pathway
Received: 28 Nov 2025; Accepted: 19 Jan 2026.
Copyright: © 2026 Destefani, Valookkaran, Bensland, Meisel and Porcheri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Cristina Porcheri
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