{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWNT5B is emerging as a multifunctional ligand with important roles in metabolism and skeletal homeostasis. In metabolic tissues, its expression is up‐regulated at early stages of adipocyte differentiation and contributes to the promotion of adipogenesis and adipocytokine‐gene expression, linking altered WNT5B function to type 2 diabetes susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, non‐canonical WNT signaling involving WNT5B appears to regulate osteogenic processes including cardiac valve calcification and osteoblast differentiation—processes further modulated by estrogen receptor signaling—thereby implicating WNT5B in bone metabolism and skeletal remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant regulation of WNT5B has been documented across a broad spectrum of malignancies. Profiling studies reveal that WNT5B is expressed in diverse cancers—including esophageal, breast, pancreatic, oral squamous, prostate, colon, liver, melanoma, and osteosarcoma—with its overexpression associating with aggressive tumor phenotypes, increased migration, invasion, and metastasis. In several studies, WNT5B has been shown to promote tumor cell proliferation and invasiveness via multiple mechanisms: by facilitating exosome‐mediated paracrine signaling, by activating small GTPases and JNK pathways, and by instigating epithelial–mesenchymal transitions. Germline variants in the WNT5B gene have furthermore been linked to poorer prognosis in colon cancer. Dysregulated WNT5B expression has also been observed in certain benign conditions, such as uterine leiomyomas and chronic lymphocytic leukemia, suggesting a broader role in cellular transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its metabolic and oncologic roles, WNT5B also functions in inflammatory and fibrotic processes. In chronic obstructive pulmonary disease (COPD), cigarette‐smoke exposure leads to an exaggerated up‐regulation of WNT5B in bronchial epithelial cells that, via TGF‐β/Smad3 signaling, induces the expression of extracellular matrix and remodeling‐related genes. Similarly, in fibrotic kidney disease, increased WNT5B expression accompanies epithelial–mesenchymal transition events in tubular epithelial cells, while stimulation of lung fibroblasts with WNT5B enhances the secretion of pro‐inflammatory cytokines through activation of non‐canonical pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic insights further underscore the complexity of WNT5B signaling. Structural analyses have identified distinct interaction motifs in WNT5B that favor binding to specific co‐receptors—differentiating its non‐canonical signaling from that of other WNT family members."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Moreover, in osteoarthritis, regulatory noncoding RNAs modulate the WNT5B axis to alter chondrocyte differentiation, emphasizing its role in degenerative joint disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Akio Kanazawa, Syuuichi Tsukada, Akihiro Sekine, et al. 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