{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CXXC4, also known as IDAX, is a multifunctional zinc‐finger protein that plays an important role in epigenetic regulation and signaling homeostasis. In one context, its CXXC domain binds to unmethylated CpG dinucleotides and directly interacts with the catalytic domain of TET2, thereby triggering caspase activation and promoting subsequent TET2 downregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In oncology, CXXC4 acts as a negative regulator of the Wnt/β‐catenin pathway. Loss or reduced expression of CXXC4 is observed in renal cell carcinoma, where deletion or low mRNA levels correlate with enhanced nuclear translocation of β‐catenin, altered transcription of genes involved in proliferation and invasion, and poorer patient survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Similarly, in gastric cancer, epigenetic silencing of CXXC4 by EZH2 or promoter hypermethylation releases its inhibitory influence on Wnt signaling, thereby promoting tumor cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In colon cancer, BMI1‐mediated suppression of CXXC4 (IDAX) contributes to enhanced Wnt activity and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its regulation of Wnt signaling, CXXC4 also modulates other pathways. It inhibits MAPK signaling by binding directly to ERK1/2 and disrupting MEK1/2–ERK1/2 interactions, a mechanism essential for its growth‐inhibitory effect in cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In pancreatic β‐cells, high glucose conditions downregulate CXXC4 expression, which is associated with increased cyclin D2 levels and enhanced cell proliferation, suggesting a critical role in glucose‐stimulated β‐cell expansion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, during stem cell differentiation, the induction of CXXC4 (or Idax) is linked to proper lineage commitment; its upregulation upon differentiation promotes neural fates while suppressing trophectoderm programs, partly through modulation of TET enzyme expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In glioma, targeting of CXXC4 by SPZ1 further supports its role as a tumor suppressor, as loss of CXXC4 function is associated with enhanced malignant progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore that CXXC4 functions as a key epigenetic and signaling regulator. Its ability to inhibit Wnt/β‐catenin and MAPK pathways, modulate TET2 levels, and influence cellular proliferation and differentiation highlights its pivotal role in preventing oncogenic transformation and in maintaining proper cell fate. Dysregulation or epigenetic silencing of CXXC4 contributes to tumor progression in multiple cancer types as well as to altered β‐cell proliferation.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Myunggon Ko, Jungeun An, Hozefa S Bandukwala, et al. 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