AFDN (afadin, adherens junction formation factor) is a nectin and actin-filament-binding protein essential for establishing and maintaining cell-cell contacts. It connects nectin to the actin cytoskeleton 1 and is critical for organizing adherens junctions and tight junctions in epithelial structures 2. AFDN functions as a RAS effector protein regulating cell adhesion, polarity, and cytoskeletal architecture 3. Mechanistically, AFDN loss disrupts intercellular tight junctions and promotes cell migration 4. It interacts with small GTPases and maintains cell-cell junction organization, preventing aberrant cellular dissemination. Clinically, AFDN deficiency has significant disease relevance. In colorectal cancer, AFDN loss promotes liver-specific metastasis by disrupting primary tumor tight junctions and increasing CXCR4 expression via JAK-STAT signaling, facilitating hepatic colonization 4. Elevated AFDN expression correlates with prolonged survival in colorectal cancer patients 4. In pediatric acute myeloid leukemia, KMT2A::AFDN fusion (6q27) is independently associated with adverse outcomes 5. Additionally, AFDN participates in alternative splicing patterns in KMT2A::AFDN oncogenic fusions 6. In viral pathology, JEV-induced DNA methylation of the Afdn promoter inhibits AFDN expression and increases blood-brain barrier permeability 7.