EPS15L1 is a constitutive component of clathrin-coated pits essential for receptor-mediated endocytosis, particularly involved in internalization of integrin beta-1 and transferrin receptor [UniProt]. Beyond its canonical endocytic role, EPS15L1 has emerged as a multi-functional protein with broader physiological significance. In immune development, EPS15L1 is essential for T lymphocyte development in zebrafish, with homozygous loss-of-function causing impaired T cell development 1. Developmentally, a frameshift deletion in EPS15L1 represents the first documented biallelic variant causing split-hand/split-foot malformation (SHFM), indicating critical roles in human limb development 2. Genetically, EPS15L1 variants on chromosome 19 associate with lymphocyte count variation in genome-wide association studies 3. In cancer biology, EPS15L1 participates in aberrant fusion events: it forms oncogenic chimeric proteins with long noncoding RNAs in various cancers, potentially regulating pyroptosis through GSDME 4, and its expression levels predict lymph node metastasis risk in hepatocellular carcinoma 5. Additionally, EPS15L1 integrates into EGFR signaling networks through interactions with CBL/CBLB ubiquitin ligases 6 and is regulated by lncRNA ABHD11-AS1 to promote thyroid cancer progression 7. These findings reveal EPS15L1 as a multifaceted endocytic adapter with developmental, immunological, and oncogenic functions.