EPS15 (epidermal growth factor receptor pathway substrate 15) is a key adaptor protein essential for clathrin-mediated endocytosis and receptor trafficking. The protein contains three N-terminal EH domains that recognize NPF-containing motifs in partner proteins, enabling promiscuous interactions with endocytic machinery components 1. EPS15 localizes to clathrin-coated pits where it interacts with AP-2 and other clathrin assembly complexes, facilitating receptor-mediated internalization of EGFR, transferrin receptor, and integrin β1 2. Beyond endocytosis, EPS15 participates in post-Golgi trafficking and plays a regulatory role in clathrin-coated pit maturation through invagination and budding 2. Recent evidence indicates EPS15 functions in autophagy-mediated responses to particulate matter exposure in airway epithelium, with reduced EPS15 expression attenuating endocytic uptake of particles 3. Additionally, EPS15 homology domain-containing proteins interact with junctophilin MORN motifs to facilitate ER-plasma membrane contact site formation at curved membrane regions 4. Clinically, EPS15 is implicated in leukemogenesis, as the EPS15 gene is recurrently rearranged with KMT2A in acute myeloid leukemia, including the 1p32/KMT2A::EPS15 fusion 5. The protein's transforming potential and ubiquitous expression underscore its importance in cell growth regulation and proliferation control 6.