{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWNT2B is emerging as a key regulator in reproductive tissues. In the rat ovary, transcripts of WNT2B are localized to the ovarian surface epithelium, suggesting a role not only in epithelial structure but also in follicular development and ovarian function, with aberrant expression noted in human ovarian cancer cell lines. Differential expression and alternative splicing of WNT2B isoforms have been reported in breast and ovarian cancer cell lines, where, for example, the WNT2B2 variant is differentially regulated by estrogen and linked to oncogenic signaling. In polycystic ovarian syndrome (PCOS) models, microRNA-mediated downregulation of WNT2B has been shown to inhibit granulosa cell proliferation, further underscoring its importance in ovarian cell biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer, WNT2B functions as a canonical Wnt ligand that activates the β‐catenin/TCF signaling cascade, promoting tumorigenesis across several epithelial cancers. Comprehensive genomic analyses have revealed that WNT2B is frequently overexpressed in malignancies such as basal cell carcinoma, gastric cancer, breast cancer, and pancreatic cancer, where its upregulation is associated with enhanced cell proliferation, invasion, metastasis, and resistance to chemotherapeutic agents. Preclinical studies targeting WNT2B have demonstrated promising antitumor activity, and genetic variants in WNT2B may serve as prognostic markers in tumors such as cutaneous melanoma and non–small cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer and reproduction, WNT2B is critically involved in multiple aspects of tissue homeostasis and systemic disease. In antiviral immunity, secretion of WNT2B by CD8⁺ T cells stabilizes β‐catenin and contributes to noncytotoxic inhibition of HIV transcription. In the gastrointestinal tract, loss-of-function mutations in WNT2B lead to severe neonatal-onset diarrhea and intestinal dysregulation due to impaired intestinal stem cell maintenance, with recent clinical observations linking WNT2B variants to an oculo‐intestinal (and possibly gonadal) syndrome. WNT2B also regulates inflammatory and regenerative responses in the liver by suppressing toll-like receptor 4 (TLR4) signaling, thereby protecting against fibrosis. Moreover, polymorphisms in WNT2B have been associated with increased risk of ischemic stroke, while altered WNT2B expression has been implicated in diabetic renal cell injury and mitochondrial dysfunction in Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of intestinal inflammation and barrier integrity, fibroblasts with elevated WNT2B expression have been shown to disrupt mucosal homeostasis. WNT2B secreted by these fibroblasts activates canonical Wnt signaling in macrophages, leading to enhanced phosphorylation of glycogen synthase kinase‑3β and increased expression and secretion of chemokines such as CXCL12. This paracrine interaction not only promotes macrophage-driven inflammatory responses by activating NF‑κB but also has been implicated in the pathogenesis of inflammatory bowel disease, as evidenced by increased WNT2B expression correlating with extensive mucosal barrier disruption and inflammation in Crohn’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Albert Ricken, Paul Lochhead, Maria Kontogiannea, et al. 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