SH3GL3 (SH3 domain containing GRB2 like 3, endophilin A3) is a multifunctional protein that serves as both a tumor suppressor and regulator of cellular processes including endocytosis and inflammation. The protein functions primarily through its SH3 domain, which mediates protein-protein interactions critical for its biological activities 12. In cancer contexts, SH3GL3 acts as a potent tumor suppressor in lung cancer and glioblastoma by inhibiting cell proliferation, migration, and invasion 12. Mechanistically, SH3GL3 suppresses STAT3 signaling by interacting with STAT3 and preventing its nuclear localization, thereby reducing glioblastoma stem cell self-renewal 2. The protein also upregulates p21 at the transcriptional level, contributing to cell cycle arrest and apoptosis induction 1. Beyond cancer, SH3GL3 has anti-inflammatory properties, attenuating acute lung inflammation by regulating the STAT3/ROS signaling pathway 3. However, in multiple myeloma, SH3GL3 paradoxically promotes cell migration, invasion, and chemoresistance through FAK/PI3K signaling pathways 4. Additionally, SH3GL3 interacts with huntingtin protein and promotes polyglutamine aggregate formation, potentially contributing to Huntington's disease pathogenesis 5. These diverse functions highlight SH3GL3's context-dependent roles in disease processes.