Folic acid inhibits the Wnt/β-catenin pathway by upregulating DKK3 to exert anti-tumor effects in cervical squamous cell carcinoma.

Cervical cancer poses a significant threat to women's health. Although folic acid (FA) has been recognized as a protective factor in cervical carcinogenesis, its precise molecular mechanisms remain incompletely understood. Here, we identify Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), an inhibitor of the Wnt signaling pathway, as a potential target of FA. This study provides systematic evidence that DKK3 expression decreases during cervical squamous epithelial carcinogenesis, showing progressive downregulation from squamous intraepithelial lesions to squamous cell carcinoma, which correlates with advanced FIGO stage and lymphovascular space invasion. Functional assays confirmed DKK3's tumor-suppressive role and therapeutic potential. DKK3 overexpression downregulated β-catenin protein levels and inhibited malignant behavior in SiHa cells, whereas its knockdown produced opposite effects. Notably, this study demonstrated for the first time that FA intervention upregulated DKK3 expression, suppressed Wnt/β-catenin signaling, leading to a reduction in β-catenin protein abundance, and exerted potent anti-tumor effects-suppressing proliferation, migration, and invasion while promoting apoptosis. Even under DKK3-knockdown conditions, FA intervention partially reversed β-catenin accumulation by enhancing residual DKK3 expression. Overall, this study establishes the prognostic and interventional value of DKK3 in cervical squamous epithelial carcinogenesis. FA intervention may serve as an effective strategy to restore DKK3 expression to inhibit the Wnt/β-catenin pathway, thereby exerting antitumor activity. Future cervical cancer prevention and treatment strategies may benefit from dynamic monitoring of DKK3 expression to identify potential beneficiaries and provide targeted FA intervention.