ARL5B (ARF like GTPase 5B) is a small G protein that primarily regulates intracellular membrane trafficking, particularly retrograde transport from endosomes to the trans-Golgi network (TGN) 1. The protein localizes to the TGN where it binds and exchanges GTP and GDP, functioning as a key regulator of endosome-to-TGN transport of membrane cargos including TGN38 and mannose-6-phosphate receptor 1. ARL5B's Golgi association is fine-tuned by heat shock cognate protein HSC70 in an ADP-dependent manner, which modulates its membrane localization 2. The protein interacts with multiple TGN-localized Rabs, Arfs, and scaffold factors like ACBD3, forming organized complexes on TGN membranes 3. Beyond trafficking, ARL5B has significant disease relevance in cancer biology, where it promotes tumor progression through metabolic reprogramming via ROCK1-SREBP1 signaling in esophageal cancer 4 and affects mitochondrial-mediated apoptosis and glycolysis in breast cancer through MDA5 signaling 5. In immune cells, ARL5B upregulation by human rhinovirus impairs macrophage bacterial clearance and phagolysosome biogenesis 6. Clinically, ARL5B represents a potential therapeutic target, as its inhibition shows promise in cancer treatment and restoration of immune function.