DKK4 (dickkopf Wnt signaling pathway inhibitor 4) is a secreted antagonist of canonical Wnt/β-catenin signaling that inhibits LRP5/6 interaction with Wnt ligands and promotes LRP5/6 internalization via KREMEN-mediated endocytosis 1. Beyond developmental roles in axial patterning and organogenesis, DKK4 plays complex, context-dependent roles in adult pathology. In colorectal cancer, DKK4 expression is paradoxically upregulated despite functioning as a Wnt antagonist 1. This occurs because partial β-catenin inhibition is required for optimal CRC progression: DKK4 secreted by cancer cells suppresses β-catenin in stromal fibroblasts, promoting myofibroblast transformation and facilitating metastasis 2. DKK4 is also elevated in renal cell carcinoma, gastric cancer, and lung cancer, where it promotes tumor growth and chemotherapy resistance 1. Notably, TFAP2E-mediated transcriptional control of DKK4 regulates fluorouracil resistance in CRC 3. In hepatoblastoma, circCLNS1A-regulated LARP1 stabilizes DKK4 mRNA, enhancing β-catenin signaling and tumorigenesis 4. Conversely, DKK4 is downregulated in hepatocellular carcinoma and Kleine-Levin syndrome 15. During endoderm differentiation, DKK4 and DKK1 function as precise Wnt modulators downstream of ALKBH5-GATA6 regulation 6.