ARL5A is a small GTPase that localizes to the trans-Golgi network (TGN) and plays a critical role in endosome-to-Golgi retrograde trafficking 12. Unlike classical ARF proteins, ARL5A lacks ADP-ribosylation enhancing activity. The protein functions as a GTP-binding regulator that facilitates recruitment of the GARP (Golgi-associated retrograde protein) complex to the TGN, which is essential for vesicle tethering and SNARE assembly during retrograde membrane transport 13. ARL5A interacts with Ragulator in response to amino acid availability, suggesting it acts as a nutrient sensor linking amino acid signaling to retrograde trafficking 4. Structurally, ARL5A undergoes typical GDP/GTP cycling characteristic of Ras-related GTPases 5. In colorectal cancer, ARL5A is significantly upregulated and promotes cell proliferation; elevated ARL5A protein levels correlate with poor prognosis 6. Notably, ARL5A also exhibits nuclear localization and interacts with heterochromatin protein 1 in a GTP-dependent manner, suggesting developmental and nuclear regulatory roles beyond its well-characterized trafficking functions 7. The related paralog ARL5B negatively regulates MDA5-dependent antiviral innate immunity independent of its GTPase activity 8.