**Background:** The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis. It comprises the canonical (β-catenin-dependent) and non-canonical (β-catenin-independent) pathways, which regulate cell proliferation, differentiation, migration, and polarity. Dysregulation of Wnt signaling is associated with a wide variety of diseases, including cancer, bone disorders, ocular diseases, cardiovascular diseases, metabolic disorders, and neurological conditions. This review aims to summarize current knowledge of Wnt signaling in stem cells, disease-associated aberrations, and novel therapeutics targeting the Wnt pathway.
**Methods:** This is a narrative review that synthesizes findings from numerous primary research articles and clinical studies. The authors describe the molecular mechanisms of canonical and non-canonical Wnt signaling, including the roles of ligands (e.g., Wnt3a, Wnt5a), receptors (Frizzled, LRP5/6, ROR), and intracellular mediators (β-catenin, Dvl, GSK-3β). They then review the evidence for Wnt signaling in various stem cell types (embryonic, hematopoietic, mesenchymal, intestinal, neural, epidermal, and cancer stem cells) and in human diseases (cancer, bone/skeletal disorders, ocular disorders, cardiovascular diseases, metabolic disorders, neurological disorders, and others). Finally, they summarize preclinical and clinical studies of Wnt-targeting therapeutics.
**Key Results:** The review highlights that Wnt signaling is critical for stem cell self-renewal and lineage differentiation in multiple tissues. For example, Wnt3a promotes hematopoietic stem cell self-renewal, while Wnt5a induces quiescence. In mesenchymal stem cells, Wnt10b facilitates osteogenesis and suppresses adipogenesis. In intestinal stem cells, Wnt signaling from Paneth cells and mesenchymal cells maintains crypt homeostasis. In neural stem cells, Wnt3a and Wnt7a promote proliferation and neurogenesis. In epidermal stem cells, Wnt/β-catenin is essential for hair follicle morphogenesis and cycling. Aberrant Wnt signaling is implicated in over 80% of colorectal tumors via APC mutations, and in up to 85% of childhood T-ALL cases with β-catenin upregulation. Mutations in SOST (sclerostin) cause sclerosteosis and van Buchem disease. LRP5 mutations are linked to osteoporosis pseudoglioma syndrome and early-onset osteoporosis. In ocular disorders, FZD4 and Norrin mutations cause familial exudative vitreoretinopathy. TCF7L2 variants are associated with type 2 diabetes, and LRP6 variants with late-onset Alzheimer's disease. Therapeutically, romosozumab (anti-sclerostin antibody) was FDA-approved in 2019 for postmenopausal osteoporosis; the FRAME trial showed a lower risk of vertebral fracture vs. placebo at 12 months, and the ARCH trial showed a 48% reduction in new vertebral fracture with romosozumab followed by alendronate vs. alendronate alone. Other anti-sclerostin antibodies (blosozumab, setrusumab) are in clinical trials. Multiple anti-cancer Wnt-targeting agents are in phase I/II trials, including PORCN inhibitors (LGK974, WNT974), CBP/β-catenin antagonists (PRI-724), ROR1/2 antagonists (cirmtuzumab), and Dkk1 antibodies (DKN-01).
**Clinical Implications:** The Wnt pathway is a promising therapeutic target for osteoporosis, osteogenesis imperfecta, and various cancers. Romosozumab's approval demonstrates the clinical utility of targeting Wnt signaling in bone disease, though cardiovascular safety concerns require monitoring. The development of cancer therapeutics targeting Wnt signaling faces challenges of on-target toxicity in normal tissues, but ongoing trials may identify cancer-specific vulnerabilities. Understanding the dual roles of Wnt signaling in stem cell maintenance and disease will guide future therapeutic strategies.