ARHGEF3 (Rho guanine nucleotide exchange factor 3) is a widely-expressed guanine nucleotide exchange factor that catalyzes nucleotide exchange on RhoA and RhoB GTPases 1, thereby positively regulating Rho protein signaling cascades. The gene is located at chromosome 3-21 1 and encodes a 526-amino acid polypeptide 1. ARHGEF3 plays important roles in multiple physiological processes. During megakaryocyte maturation, ARHGEF3 is dramatically upregulated and influences platelet function; a promoter SNP (rs1354034) acts as an expression quantitative locus associated with platelet activation and mean platelet volume in humans 2. In bone metabolism, ARHGEF3 knockdown reduces expression of osteoprotegerin in osteoblasts, suggesting involvement in bone homeostasis 3. ARHGEF3 has emerging clinical significance in multiple disease contexts. In osteosarcoma, ARHGEF3 is downregulated and correlates with increased invasion, metastasis, and proliferation, positioning it as a potential therapeutic target 4. The gene exhibits conserved antiviral properties across species, with ARHGEF3 overexpression inhibiting hepatitis C virus and flavivirus (yellow fever and Zika) replication in both humans and rhesus macaques 5. ARHGEF3 is also implicated in Hirschsprung disease susceptibility through genetic variants within RET-dependent loci 6. Additionally, exosomal miR-1911-5p regulates ARHGEF3 to promote macrophage M2 polarization and cisplatin resistance in gastric cancer 7.