WNT5A is a secreted ligand of the Wnt family that activates frizzled receptors to regulate both canonical and non-canonical Wnt signaling pathways. In canonical signaling via FZD4, it promotes β-catenin activation, while through ROR2 or FZD5, it inhibits canonical signaling and activates β-catenin-independent pathways [UniProt]. WNT5A functions as a context-dependent regulator: it suppresses canonical Wnt signaling to enable chondrogenesis and exhibits tumor-suppressive properties in some contexts, decreasing carcinoma cell proliferation and invasiveness 1. However, emerging evidence reveals WNT5A's prominent role in cancer progression through stromal interactions. Cancer-associated fibroblasts (CAFs) serve as major WNT5A producers, with CTHRC1+ CAFs promoting epithelial-mesenchymal transition (EMT) and colorectal cancer invasiveness by upregulating MSLN expression 2. Hypoxia-induced fibroblasts similarly produce WNT5A, which maintains a pro-tumoral microenvironment while suppressing angiogenesis 3. WNT5A also promotes M2 polarization of tumor-associated macrophages via IL-10 secretion through CaKMII-ERK1/2-STAT3 pathway activation, enhancing colorectal cancer growth and metastasis 4. In breast cancer, CAF-derived WNT5A activates FZD5/NF-κB/ERK signaling in endothelial cells to promote VEGF-independent angiogenesis 5. Beyond cancer, WNT5A participates in fibrotic diseases: its non-canonical signaling via CD146 and JNK drives renal fibrosis progression following acute kidney injury 6, while Wnt5a/Wnt11 promote cardiac fibrosis through FZD5-EGFR crosstalk under pressure overload 7. Mutations in WNT5A cause autosomal dominant Robinow syndrome, highlighting its role in skeletal development.