Fzd6, a member of the Frizzled family of G protein-coupled receptors, is a key mediator in the Wnt signaling pathway. The Wnt pathway plays fundamental roles in cell differentiation, organism development, and tissue polarity during development [2].

In various disease-related studies, knockout or knockdown of Fzd6 has shown distinct effects. In melanoma, knockout or knockdown of Fzd6 does not impact cell proliferation but significantly reduces the invasive ability of melanoma cells and lung metastasis in the Pten/BRaf mouse model, with canonical Wnt signaling and epithelial-mesenchymal pathway involved in this invasive phenotype [1]. In osteoporotic mice, Fzd6 expression was decreased in adipose-derived stem cells (ASCs). Fzd6 silencing down-regulated the osteogenic ability of ASCs in vitro, while overexpression rescued the impaired osteogenic capacity both in vitro and in vivo [3]. In esophageal squamous cell carcinoma (ESCC), overexpression of Fzd6 predicted poor overall survival and progression-free survival, and knockdown of Fzd6 could significantly inhibit the proliferation of ESCC cells [4]. In acute myeloid leukemia (AML), high expression of Fzd6 was observed in most cell lines and patients, associated with shorter overall survival, and its predictive effect on OS could be reversed by hematopoietic stem cell transplantation [6]. In lipopolysaccharide-induced depression-like mice, the Fzd6 mutation enhanced depression-like behavior, increased pro-inflammatory cytokines, decreased anti-inflammatory cytokines, and caused intestinal flora disturbance [5].

In conclusion, Fzd6 is crucial in the Wnt signaling pathway, and its dysregulation is associated with multiple diseases including melanoma, osteoporosis, ESCC, AML, and depression-like conditions. Studies using gene knockout or knockdown models in mice have been instrumental in revealing its role in these disease-related biological processes, providing insights into potential therapeutic targets for these diseases.