EPN2 (epsin 2) is a clathrin-binding adaptor protein that functions as a ubiquitin-dependent endocytic regulator with critical roles in both cellular trafficking and disease pathogenesis. Structurally, EPN2 contains a ubiquitin-interacting motif domain that enables binding to ubiquitinated cargo proteins, facilitating their internalization via clathrin-coated vesicles 1. Beyond canonical endocytosis, EPN2 functions as a negative regulator of angiogenesis; miR-1224-mediated suppression of EPN2 enhances tube formation in endothelial cells by derepressing VEGF signaling and activating Notch signaling 2. In atherosclerosis pathogenesis, myeloid-specific EPN2 promotes disease progression by mediating ubiquitin-dependent internalization and downregulation of LRP-1 (LDLR-related protein 1), an efferocytosis receptor with antiatherosclerotic properties 1. This mechanism suppresses anti-inflammatory macrophage function and foam cell clearance, thereby amplifying lesional inflammation. Clinically, EPN2 emerges as a candidate therapeutic target in multiple conditions. It is identified as a hub gene in perioperative neurocognitive disorders pathogenesis, with potential involvement in insulin-responsive neuroprotection 3. Additionally, EPN2 expression associates with cortical structural damage and cognitive decline in subcortical ischemic vascular disease patients 4. EPN2 also contributes to hepatocellular carcinoma progression through indirect mechanisms involving angiogenesis regulation 5. Finally, EPN2 participates in endosomal STAT3 signaling required for IL-6-mediated transcriptional activation 6.