ARHGEF19 is a Rho guanine nucleotide exchange factor that functions as a GEF for RhoA GTPase and regulates actin cytoskeleton organization through the Wnt signaling pathway and planar cell polarity pathway 1. Beyond its canonical RhoA activation, ARHGEF19 activates MAPK/ERK signaling in cancer cells through a RhoA-independent mechanism involving direct interaction with BRAF kinase via its DH and PH domains 2. ARHGEF19 is highly expressed in multiple cancer types and promotes tumor progression: in breast cancer, it enhances cell proliferation and suppresses apoptosis via MAPK pathway activation 3; in small cell lung cancer, it ranks first among RhoGEFs and promotes cell growth through MAPK/ERK signaling 4; in non-small cell lung cancer, elevated ARHGEF19 expression correlates with poor survival, lymph node metastasis, and distant metastasis 2. In hepatocellular carcinoma, miR-503 suppresses metastasis by targeting ARHGEF19 5. Recent network analysis suggests ARHGEF19 aberrations contribute to NSCLC tumorigenesis through impaired MAPK signaling and disrupted cytoskeleton organization 6. ARHGEF19 variants also associate with orofacial cleft development 7 and potentially with neurodevelopmental disorders like specific language impairment 8. ARHGEF19 represents a promising therapeutic target in multiple cancers.