Wif1, short for Wnt inhibitory factor 1, is a secreted antagonist of the Wnt signaling pathway. It directly binds to Wnt ligands, preventing their interaction with membrane-bound receptors, thus regulating the Wnt/β-catenin pathway which is crucial for embryonic development, tissue homeostasis, and is often dysregulated in diseases [4].

In prostate cancer, Wif1 acts as a tumor suppressor. It inhibits Wnt/β-catenin signaling, promotes apoptosis by regulating anti-and pro-apoptotic proteins, and suppresses epithelial-mesenchymal transition and metastasis [1]. In cervical cancer, endometrial cancer, and NSCLC, Wif1 is frequently downregulated due to promoter methylation. Restoring its expression through demethylation agents can inhibit cancer cell proliferation, induce apoptosis, and affect downstream genes in the Wnt/β-catenin pathway [2,3,5]. In podocytes, loss of CLDN5 deregulates Wif1, activating Wnt signaling and contributing to kidney disease, while systemic delivery of Wif1 suppresses disease progression [6]. In neural and glioma stem cells, Wif1 is upregulated by BMP4, and it decreases the cell cycle and inhibits proliferation of neural stem cells and glioma cells [7]. In diabetic retinopathy, Wif1 protects photoreceptor cells by inhibiting the Wnt/β-catenin-HIF-1α-Glut1 glycolytic pathway, reducing oxidative stress [8].

In summary, Wif1 is a key regulator of the Wnt signaling pathway. Its dysregulation, often due to promoter methylation, is involved in various cancers, kidney disease, and diabetic retinopathy. Understanding its function through different research models, such as in vivo studies on cell lines and animal models, provides insights into disease mechanisms and potential therapeutic targets for these diseases.