RUFY1 (RUN and FYVE domain containing 1) is a multifunctional endosomal adapter protein that coordinates vesicular trafficking between endosomes and the trans-Golgi network (TGN). Mechanistically, RUFY1 functions as a dual effector of the small GTPases Rab4 and Rab14, mediating cooperative interactions that enable endosomal tethering and fusion 1. The protein localizes to early endosomes through its FYVE domain's binding of phosphatidylinositol 3-phosphate 2, and it interacts with the dynein-dynactin motor complex to regulate cargo-selective retrieval 3. RUFY1 is recruited to endosomal membranes in a Rab14-dependent manner, with subsequent Rab4 binding enabling endosomal clustering 1. A key function involves mediating retrieval of the cation-independent mannose-6-phosphate receptor (CI-M6PR) from endosomes to the TGN, ensuring proper sorting of hydrolases to lysosomes 3. RUFY1 is recruited to early endosomes in an EGFR-dependent manner and regulates EGFR trafficking 4. Clinically, RUFY1 has emerged in multiple disease contexts: it is identified as a genetic risk locus for antipsychotic treatment response in schizophrenia through genetic-epigenetic interactions affecting cortical morphology 5, and harbors gene fusions (RUFY1::RAF1) in triple wild-type melanomas with TERT mutations, potentially providing therapeutic targets 6.