WNT5B is a secreted signaling ligand that activates frizzled family receptors to regulate both canonical and non-canonical Wnt pathways 1. The protein functions as a developmental signaling molecule affecting tissue region specification and cell differentiation, including roles in chondrocyte, muscle, and neuron development [UniProt]. WNT5B is a β-catenin-independent ligand 2 that primarily signals through the planar cell polarity (PCP) pathway via FZD3-DVL3-RAC1-JNK activation 3. Clinically, WNT5B expression correlates with malignancy across multiple cancer types. In osteosarcoma, WNT5B is the most abundant Wnt ligand and drives cancer stem cell expansion, methotrexate chemoresistance, and lung/liver metastasis through SOX2 induction and HYAL1-mediated extracellular matrix remodeling 4. In non-small cell lung cancer, WNT5B overexpression associates with advanced TNM stage, lymph node metastasis, and poor prognosis, promoting malignant phenotype via FZD3-DVL3-RAC1-PCP-JNK signaling 3. In colorectal cancer, KRAS-driven TFCP2 transcription factor upregulates WNT5B to transform carcinoma-associated fibroblasts into lipid-laden cells that produce tumor-promoting VEGFA 5. However, in non-malignant contexts, WNT5B carried by exosomes activates alternative Wnt-YAP signaling to enhance chondrocyte proliferation and migration 6, suggesting context-dependent functional roles in tissue regeneration versus malignant progression.