LRP6 (Low-density lipoprotein receptor-related protein 6) functions as a critical cell-surface co-receptor in the canonical Wnt/β-catenin signaling pathway 1. The protein forms part of the Wnt-Frizzled-LRP6 complex that triggers β-catenin signaling by promoting the formation of receptor-ligand signalosomes, which recruit DVL1 polymers and the AXIN1/GSK3B complex to inhibit β-catenin degradation 2. LRP6 expression and activity are regulated by ubiquitination, with the USP46 complex deubiquitylating LRP6 to maintain its steady-state levels and promote Wnt signaling 2. The receptor plays essential roles in bone homeostasis, with mutations affecting bone mass in conditions like osteoporosis-pseudoglioma syndrome and high-bone mass phenotypes 3. In cardiovascular disease, LRP6 demonstrates opposing roles: downregulation promotes beneficial cardiomyocyte proliferation and heart regeneration after myocardial infarction through the ING5/P21 pathway 4, while cooperation with Frizzled receptors in cardiac fibroblasts promotes pathological fibrosis via NF-κB signaling 5. Additionally, LRP6 serves as a blood-brain barrier transcytosis receptor for engineered AAV9 vectors 6 and influences vascular calcification through interactions with miR-126-3p and DKK1 7.