ARHGEF5 (Rho guanine nucleotide exchange factor 5) is a Dbl-family guanine nucleotide exchange factor that strongly activates RhoA and RhoB, while weakly activating RhoC and RhoG 1. It regulates cell shape and actin cytoskeletal organization by promoting loss of actin stress fibers and formation of membrane ruffles and filopodia 2. ARHGEF5 is required for immature dendritic cell migration in response to MIP1α, as demonstrated in Arhgef5-null mice that showed abrogated chemotaxis and impaired skin-to-lymph node migration of dendritic cells 1. Clinically, ARHGEF5 functions as a proto-oncogene in multiple malignancies. In lung adenocarcinoma, ARHGEF5 elevation correlates with increased tumor grade and pathologic stage, promoting tumorigenesis through MMP-2 and cyclin D1 upregulation via Src-Akt-NF-κB signaling 3. In colorectal cancer, ARHGEF5 promotes tumor malignancy specifically in mesenchymal-like cells through epithelial-mesenchymal transition (EMT) by activating the Rho-ROCK and PI3K-Akt pathways 4. High ARHGEF5 expression combined with EMT markers predicts poor prognosis across multiple cancer types 5. Additionally, ARHGEF5 is upregulated during osteoclast differentiation and represents a potential therapeutic target for osteoporosis 6, while elevated expression associates with unfavorable outcomes in hepatitis C-induced liver fibrosis 7.