WIF1 (Wnt inhibitory factor 1) is a secreted protein that functions as a negative regulator of canonical Wnt signaling by binding to WNT proteins and inhibiting their activities 1. The protein operates as a physiologic inhibitor of the Wnt canonical pathway, with expression localized to the extracellular region and cell surface 1. Mechanistically, WIF1 suppresses Wnt pathway activation by preventing WNT ligand engagement with receptors. In oligodendrocyte precursor cells (OPCs), aberrant Wnt signaling leads to increased WIF1 secretion, which interferes with Wnt ligand function on endothelial tight junction proteins, disrupting blood-brain barrier integrity 2. WIF1 expression is upregulated as a compensatory marker of Wnt pathway activation, as demonstrated in MS models where WIF1 marks activated OPCs 3. Clinically, WIF1 functions as a tumor suppressor gene. Its expression correlates positively with survival probability in bladder cancer patients 4. Frequent epigenetic silencing through DNA methylation occurs in mantle cell lymphoma (82% of tumors), contributing to constitutive Wnt pathway activation and uncontrolled cell growth 1. WIF1 overexpression inhibits cancer cell proliferation and migration 4. Additionally, WIF1 ameliorates diabetic retinopathy by suppressing VEGFA expression and restoring mitochondrial function through AMPK/mTOR pathway modulation 5. WIF1 downregulation in lung cancer associates with tumor progression 6.