RHOU (ras homolog family member U) is an atypical Rho family GTPase that functions as a key regulator of cytoskeletal dynamics and cellular morphology. RHOU binds to and activates protein kinase PAK1 1, playing central roles in regulating cell morphology, cytoskeletal organization, and focal adhesion assembly during cell migration 1234. Additionally, RHOU stimulates quiescent cells to re-enter the cell cycle 1. Mechanistically, RHOU exhibits constitutively high intrinsic guanine nucleotide exchange activity with no detectable GTPase activity, maintaining a predominantly GTP-bound state 5. Unlike classical Rho GTPases, RHOU possesses atypical N- and C-terminal extensions and undergoes palmitoylation rather than prenylation for membrane association 6. RHOU function requires homodimerization through its C-terminal extension, with palmitoylation essential for self-association and PAK activation 7. Pathologically, RHOU expression is upregulated during cellular senescence, where it orchestrates actin cytoskeleton remodeling to establish senescence-associated cell enlargement and the pro-inflammatory secretory phenotype through GATA4/YAP-mediated regulation 8. Developmentally, RHOU is induced by the non-canonical Wnt pathway and is necessary for neural crest cell migration 9. Transcriptionally, RHOU is regulated by both STAT3 and Wnt signaling pathways 10.