ARHGAP21 (Rho GTPase activating protein 21) functions as a GTPase-activating protein with specificity for RHOA, RhoC, and CDC42, serving as a master regulator of multiple cellular processes 12. The protein negatively regulates Rho GTPases by enhancing their intrinsic GTPase activity, thereby controlling cytoskeletal dynamics and cellular organization 3. Mechanistically, ARHGAP21 operates through several pathways including the PI3K/Akt signaling cascade and functions within membrane-associated regulatory complexes involving β-Arrestin1 and CDC42 45. The protein plays critical roles in cell adhesion, migration, Golgi regulation, and three-dimensional glandular morphogenesis 15. Disease relevance includes involvement in cancer progression, where ARHGAP21 promotes proliferation and migration in cholangiocarcinoma and prostate adenocarcinoma cells 42. Additionally, ARHGAP21 haploinsufficiency causes hematopoietic defects including impaired stem cell function and erythroid differentiation 3. Clinical significance extends to genetic association with mandibular prognathism, where a rare missense variant (Gly1121Ser) shows nearly complete penetrance in affected families 6. The protein also influences immune cell infiltration and may serve as a therapeutic target given its correlation with drug susceptibility in cancer treatment 4.