EPB41L3 (erythrocyte membrane protein band 4.1 like 3), also known as DAL-1, encodes a neuronally enriched membrane-cytoskeleton adaptor protein functioning as a tumor suppressor. Primary function: EPB41L3 inhibits cell proliferation and promotes apoptosis 1, playing critical roles in cell spreading, migration, and cytoskeletal scaffolding that support oligodendrocyte-axon adhesions essential for proper myelination 2. Mechanism: The protein modulates protein arginine N-methyltransferase activity and is regulated by transcription factors like CDC5L 1. EPB41L3 influences extracellular matrix and adhesion-related gene expression; FOXA1 O-GlcNAcylation promotes repression of EPB41L3 in breast cancer metastasis 3. Disease relevance: EPB41L3 is frequently silenced through promoter hypermethylation in gastric cancer and cervical neoplasia, contributing to disease progression 1, 4. Biallelic EPB41L3 loss-of-function variants cause autosomal recessive developmental disorder with seizures, intellectual disability, hypotonia, and delayed myelination 2. A genetic locus containing EPB41L3 is associated with lacunar stroke risk 5. Clinical significance: EPB41L3 DNA methylation serves as a biomarker for cervical precancers in HPV-positive women 6, 7, while reduced expression predicts poor gastric cancer prognosis 1. Epigenetic reactivation via demethylation agents shows tumor-suppressive potential 8.