EPN3 (epsin 3) is an endocytic adapter protein that functions as a multifaceted oncogene across multiple cancer types. As an essential component of clathrin-mediated endocytosis, EPN3 regulates receptor trafficking and stability at the plasma membrane and in endosomal compartments 1. Primary Function and Mechanism: EPN3 promotes cancer progression through distinct but interconnected mechanisms. In lung cancer, EPN3 directly interacts with EGFR, enhancing its recycling to the plasma membrane while preventing lysosomal degradation, thereby sustaining downstream signaling and promoting cell proliferation and migration 1. In breast cancer, EPN3 drives partial epithelial-to-mesenchymal transition (EMT) by increasing E-cadherin endocytosis and activating β-catenin/TCF4 signaling, establishing a TGFβ-dependent autocrine loop that confers cellular plasticity 2. EPN3 also activates NF-κB signaling in ER-positive breast cancer and JAK1/2-STAT3 signaling in NSCLC 34. Disease Relevance: EPN3 expression is significantly upregulated in NSCLC, breast cancer, and glioblastoma tissues, correlating with poor prognosis and shorter overall survival 135. Additionally, EPN3 promotes cellular senescence through ROS-mediated DNA damage in a p53-dependent manner 6. Notably, EPN3 enhances TKI resistance in EGFR-driven NSCLC regardless of tyrosine kinase domain mutations 1. Clinical Significance: EPN3 represents a promising therapeutic target, with potential for overcoming drug resistance in cancer and modulating senescence programs.