RHOBTB3 is a Rab9-regulated ATPase with dual functions in vesicular transport and protein degradation. As a retrograde transport regulator, RHOBTB3 mediates endosome-to-Golgi transport by binding specifically to Rab9 and facilitating mannose 6-phosphate receptor trafficking through vesicle docking at the Golgi 1. Its intrinsic ATPase activity is autoinhibited but activated by Rab9 interaction [UniProt annotation]. Beyond vesicular transport, RHOBTB3 functions as a ubiquitin ligase adaptor regulating multiple signaling pathways. It promotes proteasomal degradation of hypoxia-inducible factor 1-alpha (HIF-1α) by scaffolding a multi-subunit complex containing PHD2 and VHL, thereby suppressing the Warburg effect and tumor growth 2. RHOBTB3 also negatively regulates autophagy by mediating AMBRA1 ubiquitination and proteasomal degradation through K27-linked ubiquitin chains 3. In cancer contexts, RHOBTB3 expression is typically reduced in renal carcinomas and inversely associated with HIF-1 signaling activation; microRNA-142-3p suppresses RhoBTB3 to promote renal cell carcinoma progression 4, while ISG20-mediated RHOBTB3 mRNA degradation enhances breast cancer stemness and immune evasion 5. RHOBTB3 is confirmed as an imprinted gene in human placenta 6, suggesting developmental significance. These findings indicate RHOBTB3 functions as a tumor suppressor through HIF-1α regulation and autophagy inhibition.