RHOBTB1 (Rho-related BTB domain containing 1) is an atypical Rho GTPase that functions primarily as a substrate adaptor protein in the Cullin-3 ubiquitin ligase system, regulating protein degradation and cellular homeostasis 1. The protein contains two BTB domains and a C-terminal domain that are essential for recruiting substrates like phosphodiesterase 5 (PDE5) for ubiquitination and proteasomal degradation 1. In vascular smooth muscle cells, RHOBTB1 acts as a PPARγ target gene that mediates cardioprotective effects by controlling PDE5 levels, thereby regulating cGMP signaling and maintaining vasodilator responsiveness 23. RHOBTB1 also interacts with ROCK1 and ROCK2 kinases through its Rho domain, and serves as a ROCK1 substrate, with phosphorylation affecting its association with Cullin-3 4. The protein functions as a tumor suppressor, regulating Golgi integrity through METTL7B and controlling breast cancer cell invasion 5. Loss of RHOBTB1 expression promotes cancer cell invasion and is associated with Golgi fragmentation 54. Additionally, RHOBTB1 is subject to epigenetic regulation, with hypomethylation linked to diminished ovarian reserve and granulosa cell apoptosis through FGF18-MAPK pathway activation 6.