Wnt2 is an evolutionarily conserved secreted-type glycoprotein belonging to the WNT family [4]. It is involved in multiple biological processes and associated with various signaling pathways such as WNT-β-catenin. Wnt2 plays important roles in development, tissue homeostasis, and is implicated in disease development [4,5]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In various disease-related studies, knockdown of Wnt2 has shown significant impacts. In esophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC), anti-WNT2 monoclonal antibody restored dendritic cell-mediated antitumour immunity and enhanced the efficacy of anti-PD-1, as CAFs-secreted Wnt2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades [1]. In skin fibrosis, knockdown of Piezo1, which acts through the Wnt2/Wnt11 pathway, ameliorated the progression of skin fibrosis [2]. In the context of liver zonation and regeneration, EC-elimination of Wnt2 and Wnt9b led to loss of β-catenin targets in zone 3 and impaired liver regeneration, while a Wnt-activating tetravalent antibody rescued these effects [3]. In gastric cancer, blocking Wnt2 using a specific monoclonal antibody disrupted the WNT2-SOX4 positive feedback loop, enhancing chemotherapeutic efficacy [5]. In myocardial infarction, knockdown of Wnt2 and Wnt4 attenuated myocardial remodeling and cardiac dysfunction, as elevated Wnt2 activates β-catenin/NF-κB signaling to promote cardiac fibrosis [6]. In atherosclerosis, shRNA screening revealed that Wnt2 signaling is required for TGF-β-mediated endothelial-to-mesenchymal transition in human aortic endothelial cells, and high levels of Wnt2 protein were found in atherosclerotic lesions of LDLR-/-mice [7].

In conclusion, Wnt2 is involved in diverse biological functions including immune regulation, tissue fibrosis, organ regeneration, and cancer development. Gene-knockout models in mice have been crucial in revealing its role in these disease areas, providing insights into potential therapeutic strategies targeting Wnt2 for treating diseases such as cancer, fibrosis, and cardiovascular diseases.